Heteroaryl Syk inhibitors

ABSTRACT

The invention relates to new substituted heteroaryls of formula (1), wherein A is selected from the group consisting of N and CH, D is CH, E is selected from the group consisting of C and N, T is C, G is selected from the group consisting of C and N, and wherein each of the broken (dotted) double bonds in ring 1 are selected from either a single bond or a double bond under the proviso that all single and double bonds of ring 1 are arranged in such a way that they all form together with ring 2 an aromatic ring system, and wherein R 1 , M and R 3  are defined according to claim  1 , and to the above compounds for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematodes, lupus nephritis and rheumatoid arthritis.

The invention relates to new substituted heteroaryls of formula 1

or of formula 1′

wherein

-   A is selected from the group consisting of N and CH-   D is CH,-   E is selected from the group consisting of C and N,-   T is C,-   G is selected from the group consisting of C and N,    and wherein each of the broken (dotted) double bonds in ring 1 are    selected from either a single bond or a double bond under the    proviso that all single and double bonds of ring 1 are arranged in    such a way that they all form together with ring 2 an aromatic ring    system,    and wherein-   M, R³ and R¹ are defined as in claim 1. Further the invention    relates to the above compounds of formula 1 or of formula 1′ for the    treatment of a disease selected from the group consisting of asthma,    COPD, allergic rhinitis, allergic dermatitis, lupus erythematodes,    lupus nephritis and rheumatoid arthritis.

1. BACKGROUND TO THE INVENTION

1.1 SYK-Inhibitors

The present invention describes new compounds that inhibit the proteinkinase Syk (spleen tyrosine kinase), the preparation and formulationthereof and their use for preparing a medicament.

Syk is an intracellular tyrosine kinase that has an important mediatorfunction in the signal transduction of different receptors in B-cells,mast cells, monocytes, macrophages, neutrophils, T-cells, dendriticcells and epithelial cells. The receptors in which Syk performs animportant function in signal transduction include for example thereceptors for IgE (FcεRI) and IgG (FcγR1) on mast cells and B cells, theB-cell receptor (BCR) and the T-cell receptor (TCR) on B- and T-cells,the ICAM1 receptor (ICAM1R) on epithelial cells of the respiratorytract, the DAP12-receptor on natural killer cells, dendritic cells andosteoclasts, the dectin 1-receptor on a subpopulation of T-helper cells(Th-17 cells), as well as the integrin receptors for β1-, β2- andβ3-integrins on neutrophils, monocytes and macrophages (Wong et al.;Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.;Expert Opion. Ther. Target (2005) 9(5); 901-921; Wang et al.; J.Immunol. (2006) 177, 6859-6870; Leib und Gut-Landmann et al.; NatureImmunology (2007) 8, 630-638; Slack et al., European J. Immunol. (2007)37, 1600-1612). The molecular processes are described best for thesignal transduction of the FcεRI. In mast cells the binding of IgE toFcεRI causes the cross-linking of IgE-receptors and the recruiting andactivation of Lyn (a tyrosine kinase from the Src family). Active Lynphoshorylates so-called ITAM motifs, which are present in many of thereceptors listed above, and thereby generates binding sites for theSH2-domain of Syk. As a result of the binding to the ITAM motif Syk isactivated and then phosphorylates various substrates which are neededfor the release of allergic and inflammatory mediators such as e.g.histamine and β-hexosamidase (βHA), as well as for the synthesis oflipid mediators, such as e.g. prostaglandins and leukotrienes.

In view of its central function in different signal transductionpathways Syk has been discussed as a therapeutic target for differentdiseases such as e.g. allergic rhinitis, asthma, autoimmune diseases,rheumatoid arthritis, osteopenia, osteoporosis, COPD and variousleukaemias and lymphomas (Wong et al.; Expert Opin. Investig. Drugs(2004) 13(7), 743-762; Ulanova et al.; Expert Opion. Ther. Target (2005)9(5); 901-921; Sigh and Masuda. Annual Reports in Medicinal Chemistry(2007) Vol 42; 379-391; Bajpai et al.; Expert Opin. Investig. Drugs(2008) Vol 15 (5); 641-659; Masuda and Schmitz; PPT (2008) Vol 21;461-467; Riccaboni et al., Drug Discovery Today (2010) Vol 00 (0);517-530; Efremov and Luarenti, Expert Opin Investig Drugs. (2011)20(5):623-36).

Allergic rhinitis and asthma are diseases associated with allergicreactions and inflammatory processes and involving different cell typessuch as e.g. Mast cells, eosinophils, T-cells and dendritic cells. Afterexposure to allergens has occurred, the high affinity immunoglobulinreceptors for IgE (FcεRI) and IgG (FcγR1) are activated and induce therelease of pro-inflammatory mediators and bronchoconstrictors. Aninhibitor of the Syk kinase activity should thus be able to inhibitthese steps.

Rheumatoid arthritis (RA) is an autoimmune disease in which the bonesand ligaments structures surrounding the joints are progressivelydestroyed. In the pathophysiology of RA, B-cells play a significantrole, as has been demonstrated for example by the therapeutic use ofrituximab, a B cell-depleting antibody. In addition to the function ofSyk in the signal transduction of the BCR (which after being stimulatedalso induces the release of pro-inflammatory mediators), Syk also playsan important part in the maturation and proliferation of B cells (Chenget al. Nature (1995) 378, 303-306, Cornall et al., PNAS (2000) 97(4),1713-1718). An inhibitor of the Syk kinase activity may thus offer atherapeutic option for the treatment of autoimmune diseases such as RAand diseases with an increased proliferation of B cells, such as e.g.B-cell lymphomas.

Chronic obstructive pulmonary disease (COPD) is characterised by asuccessive deterioration in lung function and chronic inflammation ofthe airways, which is initiated and produced by noxious substances ofall kinds and contributes to the maintenance of the course of thedisease. At a cellular level, in COPD there is in particular amultiplication of T-lymphocytes, neutrophils, granulocytes andmacrophages. In particular, there is an increase in the number ofCD8-positive lymphocytes, that is directly connected with the impairmentof lung function. Another characteristic of COPD are acutedeteriorations in lung function (exacerbations), characterised by viral(e.g. Rhinovirus), or bacterial (e.g. Streptococcus pneumoniae,Haemophilus influenzae and Moraxella catarrhalis) infections.

In view of the pro-inflammatory function of Syk in macrophages, T-cellsand neutrophils as described above (see: Wong et al.; Expert Opin.Investig. Drugs (2004) 13(7), 743-762; and references cited therein) aninhibitor of the Syk kinase activity could be a new therapeutic approachto the treatment of the inflammatory processes that underlie COPD. Ithas also been shown that Syk in epithelial cells of the respiratorytract is involved in the ICAM1R-mediated uptake and subsequentreplication of the Rhinovirus and that a si-RNA against Syk blocks thesesteps (Wang et al.; J. Immunol. (2006) 177, 6859-6870; Lau et al.; J.Immunol. (2008) 180, 870-880). Thus, an inhibitor of the Syk kinaseactivity could also be used therapeutically in exacerbations caused byRhinoviruses.

Various studies suggest that Syk is involved in the malignanttransformation of lymphocytes (summarised in Sigh and Masuda, AnnualReports in Medicinal Chemistry (2007) Vol 42; 379-391). A TEL-Syk fusionprotein with a constitutive Syk activity transformed B cells of apatient with myelodysplastic syndrome, a constitutively active ITK-Sykfusion protein was isolated from patients with peripheral T-celllymphomas (PTCL). Moreover, constitutively active Syk was found inB-cell lymphoma cells of patients, especially in B-lineage acutelymphoblastic leukemia (B-ALL), follicular lymphoma (FL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphomas and B cell Non-HodgkinLymphomas (NHLs) as well as in acute myeloid leukemia (AML). On thebasis of these data it seems that Syk is a proto-oncogene inhaematopoietic cells and represents a potential target for the treatmentof certain leukaemias and lymphomas.

Idiophathic thrombocytopenic purpura (ITP) is an autoimmune disease inwhich IgG autoantibodies against antigens present on platelets bind toand destroy platelets. Patients with ITP have an accelerated clearenceof circulating IgG-coated platelets via macrophages in the spleen andthe liver. In view of the pro-inflammatory FcγR-mediated function of Sykin macrophages an inhibitor of Syk is considered to have a therapeuticbenefit in FcγR-mediated cytopenias like ITP. Indeed the Syk inhibitorR788 (R406) improved platelet counts in a single center, oben labelstudy in patients with ITP (Podolanczuk et al; Blood (2009) 113,3154-3169).

Bullous pemphigoid (Ujiie et al. Journal of Dermatology 2010; 37:194-204) is a chronic, autoimmune, subepidermal, blistering skin diseasethat rarely involves mucous membranes. Bullous pemphigoid ischaracterized by the presence of immunoglobulin G (IgG) autoantibodiesspecific for the hemidesmosomal bullous pemphigoid antigens BP230(BPAg1) and BP180 (BPAg2). Pemphigus vulgaris (Venugopal et al.Dermatol. Clin. 2011; 29:373-80) is a chronic blistering skin diseasewith skin lesions that are rarely pruritic, but which are often painful.Pemphigus vulgaris is an autoimmune disease caused by IgG autoantibodiesdirected against both desmoglein 1 and desmoglein 3 resulting in theloss of cohesion between keratinocytes in the epidermis. It ischaracterized by extensive flaccid blisters and mucocutaneous erosions.In both diseases IgG autoantibodies bind to Fc receptor gamma (FcRγ) andactivate FcRγ and downstream signaling via Syk kinase. Thus, aninhibitor of the Syk kinase activity which blocks downstream signallingof the FcRg could be used therapeutically to treat patients with bullouspemphigoid and pemphigus vulgaris.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whichcan affect basically any organ of the body. It is characterised by amultisystem inflammation of the microvascular and the presence ofautoantibodies. FcγR-deficient mice are protected from several aspectsof SLE in disease-related preclinical models, suggesting that aninhibitor of Syk can have a therapeutic benefit in SLE in view of thepro-inflammatory FcγR-mediated function of Syk in various cells.

1.2 Prior Art

1,6-Naphthyridines are known as SYK-inhibitors. For example U.S. Pat.No. 3,928,367, U.S. Pat. No. 4,017,500, U.S. Pat. No. 4,115,395 and U.S.Pat. No. 4,260,759 describe 5-amino-1,6-naphthyridines with anantifungal and antibacterial activity. Further, WO 9918077 describes5-piperazinyl-1,6-naphthyridines as serotonin antagonists. Additionally,U.S. Pat. No. 7,321,041 describes substituted 1,6-naphthyridines asSYK-inhibitors, however these 1,6-naphthyridines have a completelydifferent substitution pattern from the compounds according to theinvention. Also WO 2011092128 discloses 1,6-naphthyridines which aresubstituted in 5- and in 7-position.

In WO 2012/167733, WO 2012/167423 and in WO 2012/123312 othernaphthryidine derivatives such as pyrido[3,4-b]pyrazines which were alsosubstituted in 5- and in 7-position have been disclosed asSYK-inhibitors.

Additionally, WO 01/83485 discloses substituted imidazopyrimidines andtriazolopyrimidines as SYK-inhibitors, whereas WO 2008/113469 disclosessubstituted imidazo- and triazolopyrimidines as GSK 3β-inhibitors.

Also quinolones are known as SYK-inhibitors. For instance, WO 2006038041and WO 2013014060 both disclose quinoline-compounds which aresubstituted in the 5- and 7-position, however the substitutionpattern—in particular in the 7-position—is completely different from theone of the compounds of formula 1 of the instant invention.

Surprisingly it has now been found that the compounds of formulas 1 and1′ and in particular the compounds of formulas 1a, 1a′, 1c, 1c′, areparticularly suitable for the treatment of respiratory complaints,allergic diseases, osteoporosis, gastrointestinal diseases, autoimmunediseases, inflammatory diseases and diseases of the peripheral orcentral nervous system, particularly for the treatment of asthma,allergic rhinitis, rheumatoid arthritis, allergic dermatitis, lupuserythematosus (SLE) and COPD, in particular because all these compoundsof the present invention show the following desired capacities:

-   -   high SYK inhibition (reflected by “low” IC₅₀-values with respect        to SYK-inhibition)    -   very low inhibition of the kinase Aurora B (reflected by “high”        IC₅₀-values with respect to inhibition of AURB)    -   low inhibition of the kinase FLT-3 (reflected by “high”        IC₅₀-values with respect to inhibition of FLT-3)    -   low inhibition of the kinase GSK3β (reflected by “high”        IC₅₀-values with respect to inhibition of GSK3β)

This was completely surprising for a person skilled in the art, sincethe compounds of formula 1 and 1′ of the instant invention have severalsignificant structural differences compared to the previously knownprior art compounds. For instance the compounds of formula 1 and 1′ ofthe instant invention differ from the previously known1,6-naphthyridines, quinolones, pyrido[3,4-b]pyrazines,imidazopyrimidines and triazolopyrimidines therein that they combine thefollowing features:

-   -   they all possess diverse core modifications in the central        bicyclic heteroaromatic ring system (for instance core        modifications resulting in benzopyrazoles etc.)    -   that they all have a methyl-group-substitution attached to        position E in formula 1 and/or 1′ and    -   that they all possess a residue of formula T

preferably a residue of formula T′

2. DESCRIPTION OF THE INVENTION

The present invention concerns compounds of formula 1

wherein

-   A is selected from the group consisting of N and CH-   D is CH-   E is selected from the group consisting of C and N,-   T is C-   G is selected from the group consisting of C and N,    and wherein each of the broken (dotted) double bonds in ring 1 are    selected from either a single bond or a double bond under the    proviso that all single and double bonds of ring 1 are arranged in    such a way that they all form together with ring 2 an aromatic ring    system,    and wherein-   M is selected from the group consisting of —CH₂—, —O—, —NH— and    —N(C₁₋₄-alkyl)-;-   R³ is selected from the group consisting of methyl and ethyl;-   Het is selected from the group consisting of-   a five- to six-membered monocyclic heterocycle with 1, 2, 3 or 4    heteroatoms each independently from one another selected from N, S    and O,-   and a nine- to eleven-membered bicyclic heterocycle with 1, 2, 3 or    4 heteroatoms each independently from one another selected from N, S    and O;-   Hetaryl is selected from the group consisting of-   a five- to six-membered monocyclic heteroaromate with 1, 2, 3 or 4    heteroatoms each independently from one another selected from N, S    and O;    and a nine- to eleven-membered bicyclic heteroaromate with 1, 2, 3    or 4 heteroatoms each independently from one another selected from    N, S and O;    and wherein-   R¹ is selected from the group consisting of-   C₆₋₁₀-aryl, Het and Hetaryl;    which is optionally further substituted by one, two or three    substituents Z,    whereby each Z is a substituent selected from the group consisting    of    —OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,    three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,    —CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,    which is optionally further substituted by one, two or three    substituents X,    whereby each X is selected from the group consisting of halogen,    —OH, oxo, —C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl,    —O—(C₁₋₄-alkylene)-Het, Het, Hetaryl, —NH₂, —NH(CH₃), —N(CH₃)₂,    whereby substituent X is optionally further substituted by one, two    or three substituents of a group selected from oxo, —OH, halogen and    C₁₋₃-alkyl,    and the pharmaceutically acceptable salts of the aforementioned    compounds.

A preferred embodiment of the instant invention relates to theaforementioned compounds of formula 1′

wherein residues A, D, E, T, G, Het, Hetaryl, R¹ and R³ are defined asmentioned above, and the pharmaceutically acceptable salts of theaforementioned compounds.

In a further preferred embodiment the instant invention concerns theaforementioned compounds of formula 1 or of formula 1′, wherein

D is CH,

and wherein E is N

and wherein

M is —CH₂—

and wherein

R³ is methyl,

and wherein

G is C (carbon)

R¹ is selected from the group consisting of

phenyl, Het and Hetaryl;

which is optionally further substituted by one, two or threesubstituents Z,

whereby each Z is a substituent selected from the group consisting of

—OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,—CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,

which is optionally further substituted by one, two or threesubstituents X,

whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, Hetaryl, —NH₂,

whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another preferred embodiment the instant invention relates to theaforementioned compounds of formula 1a

or of formula 1a′

whereinR¹ is selected from the group consisting ofphenyl, Het and Hetaryl;which is optionally further substituted by one, two or threesubstituents Z,whereby each Z is a substituent selected from the group consisting of—OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,—CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,which is optionally further substituted by one, two or threesubstituents X,whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, Hetaryl, —NH₂,whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further preferred embodiment the invention relates to compounds ofthe above-mentioned formula 1a or of formula 1a′, wherein R¹ is

-   -   a) either selected from the group consisting of Het and Hetaryl;    -   which is optionally further substituted by one, two or three        substituents Z,

-   whereby each Z is a substituent selected from the group consisting    of —OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl,    —C₁₋₆-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl,    —CO—N(CH₃)₂, —CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl),    —O-Het,    which is optionally further substituted by one, two or three    substituents X,    whereby each X is selected from the group consisting of halogen,    oxo, —C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl,    —O—(C₁₋₄-alkylene)-Het, Het, Hetaryl, —NH₂,    -   whereby substituent X is optionally further substituted by one,        two or three substituents of a group selected from oxo, methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,        or wherein R¹ is        b) phenyl,        which is optionally further substituted by one, two or three        substituents Z,

-   whereby each Z is a substituent selected from the group consisting    of, —CN, halogen, —C₁₋₆-alkyl, —(C₁₋₃-alkylene)-Hetaryl,    —(C₁₋₃-alkylene)-Het, —C₁₋₆-haloalkyl, three- to seven-membered    cycloalkyl, Het, Hetaryl,    which is optionally further substituted by one, two or three    substituents X,    whereby each X is selected from the group consisting of halogen, oxo    and —C₁₋₄-alkyl,    -   and the pharmaceutically acceptable salts of the aforementioned        compounds.

In another preferred embodiment the invention relates to compounds ofthe above-mentioned formula 1a or of formula 1a′, wherein

R¹ is either

-   -   a monocyclic five- to six-membered heteroaromate with 1, 2 or 3        heteroatoms each independently from one another selected from        the group consisting of N, O and S,    -   or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4        heteroatoms each independently from one another selected from        the group consisting of N, O and S,        wherein this R¹-residue is attached to the rest of the molecule        either via a C-atom or via an N-atom and is optionally further        substituted by one, two or three substituents Z,        whereby each Z is a substituent selected from the group        consisting of        —OH, oxo, —CN, halogen, -methyl, -ethyl, n-propyl, isopropyl,        n-butyl, isobutyl, tert-butyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,        three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,        —CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,        which is optionally further substituted by one, two or three        substituents X,        whereby each X is selected from the group consisting of halogen,        oxo, —C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl,        —O—(C₁₋₄-alkylene)-Het, Het, Hetaryl, —NH₂,        whereby substituent X is optionally further substituted by one,        two or three substituents of a group selected from oxo, methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,        and the pharmaceutically acceptable salts of the aforementioned        compounds.

In a further preferred embodiment the invention relates to the abovecompounds of the aforementioned formula 1a or formula 1a′, wherein

R¹ is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl,pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl,

wherein this R¹-residue is attached to the rest of the molecule eithervia a C-atom or via an N-atom and is optionally further substituted byone, two or three substituents Z,

whereby each Z is a substituent selected from the group consisting of

—OH, oxo, —CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, —O— methyl, —O-ethyl, O-propyl, O-butyl,—C₁₋₃-haloalkyl, three-, four, five- or six-membered cycloalkyl, Het,Hetaryl, —CO—N(CH₃)₂, —CO—NHCH₃, —CO—NH₂,—(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,which is optionally further substituted by one, two or threesubstituents X,whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, Hetaryl, —NH₂,whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and thepharmaceutically acceptable salts of the aforementioned compounds.

In another preferred embodiment the invention concerns the abovecompounds of the aformementioned formula 1a or of formula 1a′, wherein

R¹ is phenyl,

which is optionally further substituted by one, two or threesubstituents Z,

whereby each Z is a substituent selected from the group consisting of

—OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆haloalkyl,three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,—CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,

which is optionally further substituted by one, two or threesubstituents X,

whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, Hetaryl, —NH₂,

whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and thepharmaceutically acceptable salts of the aforementioned compounds.

In a particularly preferred embodiment the instant invention relates tothe above compounds of the aforementioned formula 1a or formula 1a′,which is selected from the group consisting of

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another preferred embodiment the instant invention concerns compoundsof formula 1c

or of formula 1c′

whereinR¹ is selected from the group consisting ofphenyl, Het and Hetaryl;which is optionally further substituted by one, two or threesubstituents Z,whereby each Z is a substituent selected from the group consisting of—OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,—CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,which is optionally further substituted by one, two or threesubstituents X,whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, —NH₂,whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and thepharmaceutically acceptable salts of the aforementioned compounds.

In a further preferred embodiment the invention relates to the abovecompounds of the aforementioned formula 1c or formula 1c′, wherein R¹ is

-   a) either selected from the group consisting of Het and Hetaryl;    -   which is optionally further substituted by one, two or three        substituents Z,    -   whereby each Z is a substituent selected from the group        consisting of —OH, oxo, —CN, halogen, —C₁₋₆-alkyl,        —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl, three- to seven-membered        cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂, —CO—NHCH₃, —CO—NH₂,        —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,    -   which is optionally further substituted by one, two or three        substituents X,    -   whereby each X is selected from the group consisting of halogen,        oxo, —C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl,        —O—(C₁₋₄-alkylene)-Het, Het, Hetaryl, —NH₂,    -   whereby substituent X is optionally further substituted by one,        two or three substituents of a group selected from oxo, methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,        or wherein R¹ is-   b) phenyl,    -   which is optionally further substituted by one, two or three        substituents Z,    -   whereby each Z is a substituent selected from the group        consisting of, —CN, halogen, —C₁₋₆-alkyl,        —(C₁₋₃-alkylene)-Hetaryl, —(C₁₋₃-alkylene)-Het, —C₁₋₆-haloalkyl,        three- to seven-membered cycloalkyl, Het, Hetaryl,    -   which is optionally further substituted by one, two or three        substituents X,    -   whereby each X is selected from the group consisting of halogen,        oxo and —C₁₋₄-alkyl,        and the pharmaceutically acceptable salts of the aforementioned        compounds.

In another preferred embodiment the invention relates to the abovecompounds of the aforementioned formula 1c or formula 1c′, wherein

-   R¹ is either    -   a monocyclic five- to six-membered heteroaromate with 1, 2 or 3        heteroatoms each independently from one another selected from        the group consisting of N, O and S,    -   or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4        heteroatoms each independently from one another selected from        the group consisting of N, O and S,        wherein this R¹-residue is attached to the rest of the molecule        either via a C-atom or via an N-atom and is optionally further        substituted by one, two or three substituents Z,        whereby each Z is a substituent selected from the group        consisting of —OH, oxo, —CN, halogen, -methyl, -ethyl, n-propyl,        isopropyl, n-butyl, isobutyl, tert-butyl, —O—C₁₋₆-alkyl,        —C₁₋₆-haloalkyl, three- to seven-membered cycloalkyl, Het,        Hetaryl, —CO—N(CH₃)₂, —CO—NHCH₃, —CO—NH₂,        —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,        which is optionally further substituted by one, two or three        substituents X,        whereby each X is selected from the group consisting of halogen,        oxo, —C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl,        —O—(C₁₋₄-alkylene)-Het, Het, —NH₂,        whereby substituent X is optionally further substituted by one,        two or three substituents of a group selected from oxo, methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,        and the pharmaceutically acceptable salts of the aforementioned        compounds.

In a further preferred embodiment the invention relates to the abovecompounds of the aforementioned formula 1c or formula 1c′, wherein

R¹ is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl,pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl,

wherein this R¹-residue is attached to the rest of the molecule eithervia a C-atom or via an N-atom and is optionally further substituted byone, two or three substituents Z,

whereby each Z is a substituent selected from the group consisting of

—OH, oxo, —CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, —O-methyl, —O-ethyl, O-propyl, O-butyl,—C₁₋₃-haloalkyl, three-, four, five- or six-membered cycloalkyl, Het,Hetaryl, —CO—N(CH₃)₂, —CO—NHCH₃, —CO—NH₂,—(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,which is optionally further substituted by one, two or threesubstituents X,whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, —NH₂,whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and thepharmaceutically acceptable salts of the aforementioned compounds.

In a further preferred embodiment the instant invention concerns theabove compounds of the aforementioned formula 1c or formula 1c′, wherein

R¹ is phenyl,

which is optionally further substituted by one, two or threesubstituents Z,

whereby each Z is a substituent selected from the group consisting of

—OH, oxo, —CN, halogen, —C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —C₁₋₆-haloalkyl,three- to seven-membered cycloalkyl, Het, Hetaryl, —CO—N(CH₃)₂,—CO—NHCH₃, —CO—NH₂, —(C₁₋₃-alkylene)-O—(C₁₋₃-alkyl), —O-Het,

which is optionally further substituted by one, two or threesubstituents X,

whereby each X is selected from the group consisting of halogen, oxo,—C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —C₁₋₄-haloalkyl, —O—(C₁₋₄-alkylene)-Het,Het, —NH₂,

whereby substituent X is optionally further substituted by one, two orthree substituents of a group selected from oxo, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a particularly preferred embodiment the instant invention relates tothe above compounds of the aforementioned formula 1c or formula 1c′,which is selected from the group consisting of

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further aspect the instant invention refers to an intermediatecompound selected from the group consisting of formula 6

-   -   of formula 7

-   -   of formula 8

-   -   and of formula 11

-   -   wherein E, D, G, T and R¹ are defined above or as defined in        claim 1 and wherein Hal is Cl or Br    -   and wherein PG is a protecting group selected from the group        consisting of benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl.

In a further aspect the instant invention refers to an intermediatecompound selected from the group consisting of

-   -   formula 5.1

-   -    and    -   of formula 10.2

In a further aspect the instant invention refers to one of theaforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) for the treatment of a disease which canbe treated by inhibition of the SYK enzyme.

In another preferred aspect the instant invention relates to one of theaforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) for the treatment of a disease selectedfrom the group consisting of allergic rhinitis, asthma, COPD, adultrespiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitisand contact dermatitis, allergic dermatitis, allergicrhinoconjunctivitis, rheumatoid arthritis, anti-phospholipid syndrome,Berger's disease, Evans's syndrome, ulcerative colitis, allergicantibody-based glomerulonephritis, granulocytopenia, Goodpasture'ssyndrome, hepatitis, Henoch-Schönlein purpura, hypersensitivityvasculitis, immunohaemolytic anaemia, autoimmune haemolytic anemia,idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergicconjunctivitis, lupus erythematodes, lupus nephritis, capsule celllymphoma, neutropenia, non-familial lateral sclerosis,artheriosclerosis, Crohn's disease, multiple sclerosis, myastheniagravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis,Sjigren's syndrome, sclerodermy, T-cell lymphoma, urticaria/angiooedema,Wegener's granulomatosis and coeliac disease.

In another preferred aspect the instant invention concerns theaforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) for the treatment of a disease selectedfrom the group consisting of asthma, COPD, allergic rhinitis, adultrespiratory distress syndrome, bronchitis, allergic dermatitis, contactdermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis,lupus erythematodes, lupus nephritis and allergic rhinoconjunctivitis.

In another particularly preferred aspect the instant invention concernsthe aforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) for the treatment of a disease selectedfrom the group consisting of asthma, COPD, allergic rhinitis, allergicdermatitis, lupus erythematodes, lupus nephritis and rheumatoidarthritis.

In another preferred aspect the instant invention concernspharmaceutical formulations which contain one or more of theaforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) and a pharmaceutically acceptableexcipient.

In another preferred aspect the instant invention concernspharmaceutical formulations which contain one or more compounds of theaforementioned compounds of formula 1 or 1′ (or of any of thesub-formulas 1a, 1a′, 1c, 1c′) in combination with an active substanceselected from the group consisting of anticholinergics, betamimetics,corticosteroids, PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists,CCR3-inhibitors, iNOS-inhibitors, CRTH2-antagonists, HMG-CoA reductaseinhibitors and NSAIDs.

3. TERMS AND DEFINITIONS USED

Unless stated otherwise, all the substituents are independent of oneanother. If for example a number of C₁₋₆-alkyl groups are possiblesubstituents at a group, in the case of three substituents, for example,C₁₋₆-alkyl could represent, independently of one another, a methyl, ann-propyl and a tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be presented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Mor3eover, the atom of the substituent following the linking point isunderstood as being the atom in position number 1. Thus for example thegroups N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl(IV) and 4-tolyl (V) are represented as follows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed at the substituent andthe valency thus freed may serve as a binding site to the rest of amolecule. Thus, for example, VI

may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

Alternatively to the * within the scope of this application X₁ is alsounderstood as being the linking point of the group R¹ to the structureof formula 1 and X₂ as being the linking point of the group R² to thestructure of formula 1.

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁₋₃-alkyl” are meant branched andunbranched alkyl groups with 1 to 3 carbon atoms. “C₁₋₄-alkyl”accordingly denotes branched and unbranched alkyl groups with 1 to 4carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred.Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl orhexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc., mayalso optionally be used for the above-mentioned groups. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groupswith 1 to 4 carbon atoms are preferred. Examples of these include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene,pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,1,2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless statedotherwise, the definitions propylene, butylene, pentylene and hexyleneinclude all the possible isomeric forms of the groups in question withthe same number of carbons. Thus, for example, propyl includes also1-methylethylene and butylene includes 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene.

If the carbon chain is substituted by a group which together with one ortwo carbon atoms of the alkylene chain forms a carbocyclic ring with 3,5 or 6 carbon atoms, this includes, inter alia, the following examplesof the rings:

By the term “C₂₋₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethenyl or vinyl, propenyl, butenyl,pentenyl or hexenyl. Unless stated otherwise, the definitions propenyl,butenyl, pentenyl and hexenyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propenyl includes 1-propenyland 2-propenyl, butenyl includes 1-, 2- and 3-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples of these include:ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1, 2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1, 3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propenylalso includes 1-methylethenylene and butenylene includes1-methylpropenylene, 1, 1-dimethylethenylene, 1, 2-dimethylethenylene.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples include:phenyl or naphthyl, the preferred aryl group being phenyl. Unlessotherwise stated, the aromatic groups may be substituted by one or moregroups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

By the term “aryl-C₁₋₆-alkylene” (including those which are part ofother groups) are meant branched and unbranched alkylene groups with 1to 6 carbon atoms, which are substituted by an aromatic ring system with6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl or1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups maybe substituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heteroaryl-C₁₋₆-alkylene” (including those which are partof other groups) are meant—even though they are already included under“aryl-C₁₋₆-alkylene”-branched and unbranched alkylene groups with 1 to 6carbon atoms, which are substituted by a heteroaryl.

If not specifically defined otherwise, a heteroaryl of this kindincludes five- or six-membered heterocyclic aromatic groups or5-10-membered, bicyclic heteroaryl rings which may contain one, two,three or four heteroatoms selected from among oxygen, sulphur andnitrogen, and contain so many conjugated double bonds that an aromaticsystem is formed. The following are examples of five- or six-memberedheterocyclic aromatic groups or bicyclic heteroaryl rings:

Unless otherwise stated, these heteroaryls may be substituted by one ormore groups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

The following are examples of heteroaryl-C₁₋₆-alkylenes:

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, which are substituted by one or more halogen atoms. By theterm “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1to 4 carbon atoms, which are substituted by one or more halogen atoms.

Alkyl groups with 1 to 4 carbon atoms are preferred. Examples include:CF₃, CHF₂, CH₂F, CH₂CF₃.

By the term “C₃₋₇-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 7 carbon atoms, if notspecifically defined otherwise. Examples include: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwisestated, the cyclic alkyl groups may be substituted by one or more groupsselected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy,fluorine, chlorine, bromine and iodine.

If not specifically defined otherwise, by the term “C₃₋₁₀-cycloalkyl”are also meant monocyclic alkyl groups with 3 to 7 carbon atoms and alsobicyclic alkyl groups with 7 to 10 carbon atoms, or monocyclic alkylgroups which are bridged by at least one C₁₋₃-carbon bridge.

By the term “heterocyclic rings” or “heterocycle” are meant, unlessstated otherwise, five-, six- or seven-membered, saturated, partiallysaturated or unsaturated heterocyclic rings which may contain one, twoor three heteroatoms, selected from among oxygen, sulphur and nitrogen,while the ring may be linked to the molecule through a carbon atom orthrough a nitrogen atom, if there is one. Although included by the term“heterocyclic rings” or “heterocycles”, the term “saturated heterocyclicring” refers to five-, six- or seven-membered saturated rings. Examplesinclude:

Although included by the term “heterocyclic rings” or “heterocyclicgroup”, the term “partially saturated heterocyclic group” refers tofive-, six- or seven-membered partially saturated rings which containone or two double bonds, without so many double bonds being producedthat an aromatic system is formed, unless specifically definedotherwise. Examples include:

Although included by the term “heterocyclic rings” or “heterocycles”,the term “heterocyclic aromatic rings”, “unsaturated heterocyclic group”or “heteroaryl” refers to five- or six-membered heterocyclic aromaticgroups or 5-10-membered, bicyclic heteroaryl rings which may containone, two, three or four heteroatoms, selected from among oxygen, sulphurand nitrogen, and contain so many conjugated double bonds that anaromatic system is formed, unless not specifically defined otherwise.Examples of five- or six-membered heterocyclic aromatic groups include:

Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may beprovided with a keto group. Examples include:

Although covered by the term “cycloalkyl”, the term “bicycliccycloalkyls” generally denotes eight-, nine- or ten-membered bicycliccarbon rings. Examples include

Although already included by the term “heterocycle”, the term “bicyclicheterocycles” generally denotes eight-, nine- or ten-membered bicyclicrings which may contain one or more heteroatoms, preferably 1-4, morepreferably 1-3, even more preferably 1-2, particularly one heteroatom,selected from among oxygen, sulphur and nitrogen, unless notspecifically defined otherwise. The ring may be linked to the moleculethrough a carbon atom of the ring or through a nitrogen atom of thering, if there is one. Examples include:

Although already included by the term “aryl”, the term “bicyclic aryl”denotes a 5-10 membered, bicyclic aryl ring which contains sufficientconjugated double bonds to form an aromatic system. One example of abicyclic aryl is naphthyl.

Although already included under “heteroaryl”, the term “bicyclicheteroaryl” denotes a 5-10 membered, bicyclic heteroaryl ring which maycontain one, two, three or four heteroatoms, selected from among oxygen,sulphur and nitrogen, and contains sufficient conjugated double bonds toform an aromatic system, unless specifically defined otherwise.

Although included by the term “bicyclic cycloalkyls” or “bicyclic aryl”,the term “fused cycloalkyl” or “fused aryl” denotes bicyclic ringswherein the bridge separating the rings denotes a direct single bond.The following are examples of a fused, bicyclic cycloalkyl:

Although included by the term “bicyclic heterocycles” or “bicyclicheteroaryls”, the term “fused bicyclic heterocycles” of “fused bicyclicheteroaryls” denotes bicyclic 5-10 membered heterorings which containone, two, three or four heteroatoms, selected from among oxygen, sulphurand nitrogen and wherein the bridge separating the rings denotes adirect single bond. The “fused bicyclic heteroaryls” moreover containsufficient conjugated double bonds to form an aromatic system. Examplesinclude pyrrolizine, indole, indolizine, isoindole, indazole, purine,quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine,pteridine, pyrimidopyrimidine,

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

Compounds of general formulas 1 or 1′ may have acid groups, mainlycarboxyl groups, and/or basic groups such as e.g. amino functions.Compounds of general formulas 1 or 1′ may therefore be present asinternal salts, as salts with pharmaceutically usable inorganic acidssuch as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonicacid or organic acids (such as for example maleic acid, fumaric acid,citric acid, tartaric acid or acetic acid) or as salts withpharmaceutically usable bases such as alkali metal or alkaline earthmetal hydroxides or carbonates, zinc or ammonium hydroxides or organicamines such as e.g. diethylamine, triethylamine, triethanolamine, interalia.

As mentioned previously, the compounds of formulas 1 or 1′ may beconverted into the salts thereof, particularly for pharmaceutical useinto the physiologically and pharmacologically acceptable salts thereof.These salts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds offormula 1 with inorganic or organic acids. On the other hand, thecompound of formulas 1 or 1′ when R is hydrogen may be converted byreaction with inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations ascounter-ion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. To prepare the alkali andalkaline earth metal salts of the compounds of formulas 1 or 1′ whereinR denotes hydrogen, it is preferable to use the alkali and alkalineearth metal hydroxides and hydrides, of which the hydroxides andhydrides of the alkali metals, particularly sodium and potassium, arepreferred, while sodium and potassium hydroxide are particularlypreferred.

The compounds of general formulas 1 or 1′ may optionally be convertedinto the salts thereof, particularly for pharmaceutical use into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Examples of suitable acids for this purpose includesuccinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

The invention relates to the compounds of formula 1 in question,optionally in the form of the individual optical isomers, mixtures ofthe individual enantiomers or racemates, in the form of the tautomers aswell as in the form of the free bases or the corresponding acid additionsalts with pharmacologically acceptable acids—such as for example acidaddition salts with hydrohalic acids—for example hydrochloric orhydrobromic acid—or organic acids—such as for example oxalic, fumaric,diglycolic or methanesulphonic acid.

The compounds of formula 1, 1a and 1c according to the invention mayoptionally be present as racemates, but may also be obtained as pureenantiomers, i.e. in the (R) or (S) form. Preferred are the compoundswith the specific stereochemistry of formula 1′, in particular thecompounds with the specific stereochemistry of one of formulas 1a′ and1c′.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, diastereomers, mixtures ofdiastereomers, mixtures of the individual enantiomers or racemates, inthe form of the tautomers as well as in the form of the free bases orthe corresponding acid addition salts with pharmacologically acceptableacids—such as for example acid addition salts with hydrohalic acids—forexample hydrochloric or hydrobromic acid—or organic acids—such as forexample oxalic, fumaric, diglycolic or methanesulphonic acid.

The invention relates to the respective compounds of formulas 1 or 1′ inthe form of the pharmacologically acceptable salts thereof. Thesepharmacologically acceptable salts of the compounds of formulas 1 or 1′may also be present in the form of their respective hydrates (e.g.Monohydrates, dihydrates, etc.) as well as in the form of theirrespective solvates.

By a hydrate of the compound according to the formulas 1 or 1′ is meant,for the purposes of the invention, a crystalline salt of the compoundaccording to formulas 1 or 1′, containing water of crystallisation.

By a solvate of the compound according to formulas 1 or 1′ is meant, forthe purposes of the invention, a crystalline salt of the compoundaccording to formulas 1 or 1′, which contains solvent molecules (e.g.Ethanol, methanol etc) in the crystal lattice.

The skilled man will be familiar with the standard methods of obtaininghydrates and solvates (e.g. recrystallisation from the correspondingsolvent or from water).

4. METHODS OF PREPARATION

The Examples according to the invention were prepared as shown inSchemes 1, 2 or 3.

D is CH,G is C or NT is CE is C or N, preferably NHal is Br or Clwith X being —B(OH)₂, -boronic acid pinacolester, -trifluoroborate or—SnBu₃PG is protecting group (e.g. benzyl, 1-phenylethyl,1-(4-methoxyphenyl)ethyl)and R¹ is as herein before defined.

D is CH,G is C or NT is CE is C or N, preferably NA is CH or NHal is Br or Clwith X being —B(OH)₂, -boronic acid pinacolester, -trifluoroborate or—SnBu₃PG is protecting group (e.g. benzyl, 1-phenylethyl,1-(4-methoxyphenyl)ethyl)and R¹ is as herein before defined.4.1. Starting Materials of Formula 2, 3, 4, 5 and 104.1.1. Synthesis of Lactams 2 from Scheme 1 and 2

Synthesis of Synthesis of(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.1 for Examples 1-3, 7-13, 17, 50-84 and(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.2 for Examples 4-6, 14-16, 18-49.

Step 1: Synthesis of(1′R,3R/S)-1-(1′-(4-Methoxyphenylethyl)-5-oxo-3-pyrrolidine carboxylicacid (mixture of diastereoisomers)

A suspension of 100 g of (R)-1-(4-methoxy-phenyl)-ethylamine and 95 gitaconic acid in 0.5 L 1-methyl-2-pyrrolidinone was heated to 80° C. for1 hour. The solution was stirred for additional 4 hours at 120° C. Thereaction mixture was cooled to 25° C. and poured into 1.5 L ofdemineralized water. The precipitate was filtered, washed withdemineralized water and dried at 50° C.

Yield: 195 g (quantitative yield) solid as a mixture of diastereoisomers

Analysis (method G): R_(t): 2.6 min and 2.7 min, (M+H)⁺: 264

Step 2: Synthesis of(R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamideas a mixture of diastereoisomers

260 g of 1,1′-carbonyldiimidazole (CDI) were added to a solution of 285g (1′R,3R/S)-1-(1′-(4-methoxyphenylethyl)-5-oxo-3-pyrrolidine carboxylicacid (mixture of diastereoisomers) in 1.4 L 2-methyltetrahydrofuran at20° C. The suspension was stirred at 20° C. for 80 minutes. 235 mLethyldiisopropylamine (DIPEA) and 130 g of N,O-dimethylhydroxylaminehydrochloride were added. The suspension was stirred for 3 hours at 20°C. Under cooling 850 mL 4M hydrochloric acid was added. The organicphase was separated and washed two times with 500 mL 1 N hydrochloricacid. The aqueous phase was reextracted two times with 500 mL ethylacetate. The combined organic phases were dried over sodium sulfate.After filtration the solvent was evaporated under reduced pressure.

Yield: 271 g (82% of theory) of(R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide(mixture of diastereoisomers) as an oil.

Analysis (method H): R_(t): 11.1 min (41 area %) and 13.8 min (59 area%), (M+H)⁺: 307

Step 3: Synthesis of(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one as amixture of diastereoisomers

530 mL of a 3M solution of methylmagnesium bromide in diethylether wereadded slowly to a cooled solution of 271 g of(R/S)—N-methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide(mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran sothat the temperature remained under 0°. After complete addition thetemperature was kept for 75 minutes at 0° C. and then warmed up to 20°C. The suspension was stirred 16 hours at 20° C. Under cooling 650 mL ofa 4M hydrochloric acid were added. The organic phase was separated andwashed with 500 mL saturated sodium carbonate solution and with 500 mLsaturated brine. The organic phase was dried over sodium sulfate. Afterfiltration the solvent was evaporated under reduced pressure.

Yield: 188 g (81% of theory) of(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one(mixture of diastereoisomers) as an oil.

Analysis (method H): R_(t): 7.4 min and 9.6 min, (M+H)⁺: 262

Step 4: Crystallization of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one underbase induced epimerization conditions

103 g of a mixture of diastereoisomers(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one weredissolved in 155 mL 1-butanol at 25° C. 18 mL benzyltrimethylammoniumhydroxide (40% solution in methanol) was added. The solution was stirredfor 30 minutes at 25° C. The solution was cooled to 0° C. Precipitationstarted. The suspension was stirred for 15 minutes at 0° C. 100 mLn-heptane was added slowly and the suspension was stirred for 30 minutesat 0° C. The addition of 100 mL portions of n-heptane was repeated 4times with subsequent stirring of the suspension at 0° C. for 30minutes. The precipitate was isolated, washed with n-heptane and driedat 50° C.

Yield: 77.1 g of a beige solid (75% of theory) with a diastereoisomericpurity of ˜95:5 (method H).

For further purification the crude product was dissolved in 310 mL2-methyl-2-butanol at 40° C. (temperature <50° C.). The solution wasslowly cooled to 0° C. Precipitation started. At 0° C. 385 mL ofn-heptane were added and the suspension was stirred for 1 hour. Theprecipitate was filtrated, washed with n-heptane and dried at 50° C.

Yield: 68.7 g (67% of theory) of a colorless solid with adiastereoisomeric purity of >99:1.

Analysis (method H): R_(t): 6.8 min, (M+H)⁺: 262

Step 4: Crystallization of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one underbase induced epimerization conditions

13.2 g of a mixture of diastereoisomers(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one weredissolved in 18 mL of 1-butanol at 25° C. The solution was cooled to 3°C. and treated with 100 mg of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one. Theresulting mixture was agitated for 15 min at 3° C.; at which point, 2.3mL benzyltrimethylammonium hydroxide (40% solution in methanol) wereadded. The solution was stirred for 30 minutes at 3° C. 64 mL n-heptanewas added slowly over 1 h at 0 to 3° C. and the suspension was stirredfor 60 minutes at 0° C. The precipitate was isolated, washed withn-heptane and dried at 3° C.

Yield: 10.6 g of a beige solid (80% of theory) with a diastereoisomericpurity of ˜98:2 (method H).

Analysis (method H): R_(t): 6.8 min, (M+H)⁺: 262

Step 5: Synthesis of(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.1

94.6 mg of dichloro (pentamethylcyclopentadienyl)-iridium(III) dimer and105 mg of (S,S)—N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine[(R,R)-TsDPEN] were dissolved in 20 mL of acetonitrile and subsequentlycharged to a slurry of 50 g of(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one and 65g of sodium formate in 500 mL of water at 25° C. The slurry was heatedto 60° C. and agitated at this temperature while sparging with nitrogenfor 3 h. The reaction was diluted at 60° C. with 500 mL of isopropylacetate and subsequently cooled to ambient temperature. The layers wereseparated, and the organic portion was washed twice with 300 mL ofwater. The organic portion was concentrated to an oily solid. Theresidual material was crystallized three times from ethyl acetate andhexanes followed by drying in a vacuum oven with a nitrogen stream at30° C.

25.4 g of a beige solid with a diastereomeric purity of >99:1

Step 5: Synthesis of(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.2

9.46 mg of dichloro (pentamethylcyclopentadienyl)-iridium(III) dimer and10.52 mg of (R,R)—N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine[(R,R)-TsDPEN] were dissolved in 1 mL of acetonitrile and subsequentlycharged to a slurry of 5 g of(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one and 6.5g of sodium formate in 50 mL of water at 25° C. The slurry was heated to60° C. and agitated at this temperature while sparging with nitrogen for3 h. The reaction was diluted at 60° C. with 50 mL of isopropyl acetateand subsequently cooled to ambient temperature. The layers wereseparated, and the organic portion was washed with 20 mL of water. Theorganic portion was concentrated to an oil. The oil was dissolved in 8mL of isopropyl acetate at reflux. The solution was cooled to ambienttemperature wherein crystallization occurred. The mixture was diluteddropwise with 10 mL of heptane at ambient temperature. The mixture wasagitated for 30 minutes. The solids were collected by filtration, washedwith a solution of 20 vol % isopropyl acetate in heptane and dried in avacuum oven with a nitrogen stream at 55° C. 3.82 g of a beige solidwith a diastereomeric purity of 99:1 Analysis (method I): R_(t): 12.9min, (M+H)⁺: 264

Synthesis of[(1S)-1-[(3R)-1-[(1S)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate2.3

To a mixture of 20.0 g of(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.2, 21.67 g p-toluenesulfonyl chloride and 0.92 gN,N-dimethylpyridin-4-amine was added 42 mL pyridine and 42 mLdichloromethane (DCM). The resulting mixture was stirred at 34° C. for18 h under argon atmosphere. The reaction mixture was diluted withisopropyl acetate and washed with water and 2M hydrochloric acid. Thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was taken up in isopropyl acetate andn-heptane. The precipitate was filtered off, washed withn-heptane/isopropyl acetate and dried to yield 19.83 g of[(1S)-1-[(3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate 2.3 as solid.

Analysis: HPLC-MS: R_(t)=0.680 min (method J), M+H=418

4.1.2. Synthesis of Boronic Acids, Boronic Esters, BF₃ Borates andStannanes with Formula 4

X.1.2.1. Synthesis of R¹-Hal 3

Synthesis of 4-Bromo-1-tert-butyl-pyrazole 3.1 for Examples 2, 18 Step1: Synthesis of 1-tert-Butyl-pyrazole

To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and26.20 g tert.-butylhydrazine hydrochloride in 230 mL ethanol was added40.0 mL conc. hydrochloric acid dropwise below 50° C., then the mixturewas stirred under reflux for 2 h. The reaction mixture was diluted withwater. The solvent was almost removed by destillation and the aqueousresidue extracted with diethylether. The combined aqueous phases werebasified with 10N sodium hydroxide solution and extracted withdiethylether. The combined organic phases were washed with saturatedbrine, dried over sodium sulfate, filtered and concentrated in vacuo toyield 21.90 g of 1-tert-butyl-pyrazole as oil.

Analysis: HPLC-MS: R_(t)=0.412 min (method A), M+H=125

Step 2: Synthesis of 4-Bromo-1-tert-butyl-pyrazole

To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL DCM was added31.5 g N-bromosuccinimide in portions between 0 and 10° C. The resultingmixture was stirred for 30 min. The reaction mixture was allowed toreach ambient temperature. The precipitate was filtered off and washedwith DCM. The combined organic extracts were washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.

Analysis: HPLC-MS: R_(t)=1.35 min (method B), M+H=203/205

Synthesis of trans4-[4-(4-Bromo-pyrazol-1-yl)-cyclohexyl]-1-methyl-piperazin-2-one 3.2 forExample 12

The starting material1-spiro[7-azoniabicyclo[2,2,1]heptane-7,4′-[1′-methyl-2′-oxo-4′-piperazinium]methane-sulphonate]was obtained as described in W2011092128.

To a solution of 506 mg of 4-bromopyrazole in 7.5 mL dimethylacetamide(DMA) was added 91 mg sodium hydride (NaH). The resulting mixture wasstirred at room temperature for 10 min, before 1.0 g of1-spiro[7-azoniabicyclo[2,2,1]heptane-7,4′-[1′-methyl-2′-oxo-4′-piperazinium]methane-sulphonate]was added and the mixture was stirred at 100° C. for 40 min. Additional70 mg NaH were added and the reaction mixture was stirred at 120° C. for40 min. The solvent was removed by destillation and the residue taken upin MeOH and purified by rpHPLC (XbridgeC18, acetonitrile/water, ammonia)to yield after lyophilisation 850 mg of trans4-[4-(4-bromo-pyrazol-1-yl)-cyclohexyl]-1-methyl-piperazin-2-one assolid.

Analysis: HPLC-MS: R_(t)=0.45 min (method C), M+H=341/343 Synthesis of5-Bromo-2-(difluoromethyl)pyridine 3.3 for Example 51

A solution of 1 g of 5-bromopyridine-2-carbaldehyde in 50 mL DCM wascooled to −70° C., then 1.55 mL diethylaminosulfurtrifluoride were addeddropwise over 20 minutes. The suspension was stirred for 30 minutes atroom temperature, then 10 mL water were added at 0° C. followed by slowaddition of 20 mL saturated NaHCO₃ (gas formation). The phases wereseparated and 2 mL of 4M HCl in dioxane were added to the organic phasewhich was concentrated in vacuo to provide 1.06 g product as yellowsolid.

Analysis: HPLC-MS: R_(t)=0.72 min (method D), M+H=208/210.

Synthesis of 7-Bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine 3.4 forExample 55

7-Bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine can be obtained asdescribed in Shah, Unmesh; Lankin, Claire M.; Boyle, Craig D.;Chackalamannil, Samuel; Greenlee, William J.; Neustadt, Bernard R.;Cohen-Williams, Mary E.; Higgins, Guy A.; Ng, Kwokei; Varty, GeoffreyB.; Zhang, Hongtao; Lachowicz, Jean E. Bioorganic and MedicinalChemistry Letters, 2008, 18, 4204-4209.

Synthesis of 6-Bromo-N,N,1-trimethyl-indole-2-carboxamide 3.5 forExample 56

A mixture of 0.68 g of 6-bromo-1-methyl-indole-2-carboxylic acid, 1.1 gof2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat(HATU) and 0.55 mL triethylamine in 2 mL N-methyl-2-pyrrolidinon (NMP)and 3 mL tetrahydrofuran (THF) was stirred at room temperature for 2 hfollowed by addition of 4.0 mL 2M dimetylamine solution in THF. Thereaction mixture was stirred at room temperature for 30 min. Thereaction mixture was diluted with DCM and washed with saturated aqueoussodium bicarbonate solution. The combined organic phases wereconcentrated in vacuo. The crude material was purified by flashchromatography (DCM→DCM: methanol 90:10) to yield 0.66 g of 6-bromo-N,N,1-trimethyl-indole-2-carboxamide 3.5 as oil.

Analysis: HPLC-MS: R_(t)=0.85 min (method E), M+H=281/283

Synthesis of 4-Bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6 forExample 70 Step 1: Synthesis of [(3R)-Tetrahydrofuran-3-yl]4-methylbenzenesulfonate

To a solution of 25.43 g (R)-tetrahydro-furan-3-ol in 60 mL pyridine and250 mL DCM was added 73.0 g of 4-methyl-benzenesulfonyl chloridefollowed by 1.0 g N,N-dimethylpyridin-4-amin. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith DCM and washed with 2M hydrochloric acid and water. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedin vacuo. The crude material was purified by flash chromatography(DCM→DCM: methanol 95:5) to yield 59.46 g [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate as oil.

Analysis: MS: M+H=243

Step 2: Synthesis of 4-Bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6

A mixture of 650 mg [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate, 400 mg 4-bromo-1H-pyrazole and 1.40 g cesiumcarbonate in 10 mL N,N-dimethylformamide (DMF) was stirred at 65° C. for6 h. Additional 20 mg 4-bromo-1H-pyrazole were added and the reactionmixture was stirred at 65° C. overnight. The reaction mixture wasdiluted with ethyl acetate and washed with brine. The combined organicphases were dried over sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography(cyclohexane/ethyl acetate 9:1→1:1) to yield 476 mg of4-bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6 as solid.

Analysis: MS: M+H=217/219

Synthesis of 4-Bromo-1-[(3R)-tetrahydrofuran-3-yl]pyrazole 3.7 forExample 74

This intermediate was prepared from (S)-tetrahydro-furan-3-ol in twosteps according to the preparation of4-bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6.

Analysis: MS: M+H=217/219

Synthesis of 4-Bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazole 3.8 forExample 79 Step 1: Synthesis of 5-Methyl-1-tetrahydropyran-4-yl-pyrazole

To a stirred mixture of 2.26 g of 1-tetrahydropyran-4-ylpyrazole in 20mL THF was added 11.14 mL of 1.6M N-butyllithium solution in hexanedropwise at −50° C. under argon atmosphere. The mixture was stirredbetween −20° to −15° C. for 1.5 h, before 1.11 mL methyl iodide wereadded dropwise. The resulting mixture was stirred between −20° to −15°C. for 1.5 h. 10 mL water were added dropwise and the mixture wasallowed to reach ambient temperature. The reaction mixture was dilutedwith water, followed by extraction with ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by rpHPLC (basic) toyield after lyophilisation 1.51 g of5-methyl-1-tetrahydropyran-4-yl-pyrazole as solid.

Analysis: HPLC-MS: R_(t)=0.61 min (method F), M+H=167

Step 2: Synthesis of 4-Bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazole3.8

To a mixture of 1.0 g of 5-methyl-1-tetrahydropyran-4-yl-pyrazole in 20mL THF and 20 mL ethyl acetate was added 1.09 g bromosuccinimide inportions between 10 and 20° C. The reaction mixture was stirred at roomtemperature for 30 min and then quenched with saturated aqueouspotassium carbonate solution. The solvent was evaporated and the residuewas purified by rpHPLC (basic) to yield after lyophilisation 1.20 g of4-bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazole 3.8 as solid.

Analysis: HPLC-MS: R_(t)=0.65 min (method F), M+H=245/247

Synthesis of 4-(4-Bromophenyl)-1-methyl-piperidine 3.9 for Example 80

To a mixture of 100 mg of 4-(4-bromophenyl)-piperidine hydrochlorid and100 mg sodium acetate in 3 mL DCM and 0.5 mL methanol was added 50 μLformaldehyde (aqueous 37%). The resulting mixture was stirred at roomtemperature for 10 min, before 155 mg sodium triacetoxyborohydride wereadded. The reaction mixture was stirred for 2 h and quenched withsaturated aqueous sodium bicarbonate solution, followed by extractionwith DCM. The combined organic phases were concentrated in vacuo toyield 88 mg of 4-(4-bromophenyl)-1-methyl-piperidine 3.9 as solid.

Analysis: HPLC-MS: R_(t)=0.38 min (method J), M+H=254/256

Synthesis of 4-(4-Bromo-3-trifluoromethyl-phenyl)-1-methyl-piperidine3.10 for Example 32

To a solution of 640 mg of4-(4-bromo-3-trifluoromethyl-phenyl)-piperidine in 16.3 mL DCM and 2.9mL methanol was added 6.40 mL formaldehyde (aqueous 37%). The resultingmixture was stirred at ambient temperature for 1 h, before cooled to 0°C. and 1.02 g sodium triacetoxyborohydride were added in portions. Thenthe reaction was allowed to warm to ambient temperature and was stirredfor 1 h. The reaction mixture was quenched with saturated aqueouspotassium carbonate solution, followed by extraction with DCM. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography (heptane/ethyl acetate/methanol) to yield 650 mg of4-(4-bromo-3-trifluoromethyl-phenyl)-1-methyl-piperidine 3.10 as oil.

Analysis: HPLC-MS: R_(t)=1.37 min (method K), M+H=323/325

Synthesis of 4-(4-Bromo-2-trifluoromethyl-phenyl)-morpholine 3.11 forExample 38

A mixture of 1.0 g of 4-bromo-2-(trifluoromethyl)aniline, 786 μLbis(2-bromoethyl)ether and 1.45 mL diisopropylamine in 3 mL DMA wasstirred in a sealed tube at 140 CC for 2 days. The reaction mixture waspoured into water and extracted with TBME. The combined organic extractswere washed with saturated aqueous sodium bicarbonate solution, driedover sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (heptane/ethylacetate/methanol) to yield 833 mg (84% per HPLC) of4-(4-bromo-2-trifluoromethyl-phenyl)-morpholine 3.11 as oil.

Analysis: HPLC-MS: R_(t)=2.37 min (method K), M+H=310/312

Synthesis of 4-Bromo-1-(4,4-difluorocyclohexyl)pyrazole 3.12 for Example10 Step 1: Synthesis ofN′-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylic acid tert-butylester

A solution of 0.99 g hydrazinecarboxylic acid tert-butyl ester in 5 mLmethanol was added dropwise to a solution of 1.0 g of4,4-difluoro-cyclohexanone in 5 mL methanol. The resulting mixture wasstirred at room temperature for 1 h. The solvent was removed bydestillation to yield 1.76 gN′-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylic acid tert-butylester as solid.

Analysis: MS: M+H=249

Step 2: Synthesis of N′-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylicacid tert-butyl ester

A mixture of 8.0 g N′-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylicacid tert-butyl ester and 800 mg palladium on carbon in 48 mL methanolwas hydrogenated at 40° C. for 16 h at 10 bar. The catalyst was removedby filtration and the solvent was evaporated in vacuo to yield 7.82 g ofN′-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester.

Analysis: MS: M−H=249

Step 3: Synthesis of (4,4-Difluoro-cyclohexyl)-hydrazine Hydrochlorid

To a mixture of 5.0 g ofN′-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylic acid tert-butyl esterin 20 mL DCM was added 40 mL 6M hydrochloric acid in isopropanol and theresulting mixture was stirred at room temperature for 12 h. The solventwas evaporated and the residue triturated with toluene. The precipitatewas filtered off and dried to yield 3.72 g of(4,4-difluoro-cyclohexyl)-hydrazine hydrochlorid as solid.

Analysis: ESI-MS: M+H=151

Step 4: Synthesis of 1-(4,4-difluorocyclohexyl)pyrazole

To a mixture of 2.04 g of (4,4-difluoro-cyclohexyl)-hydrazinehydrochlorid in 15 mL ethanol was added 3.50 mL conc. hydrochloric acidfollowed by 1.80 g 1,1,3,3-tetramethoxypropane, then the mixture wasrefluxed for 1h. The reaction mixture was diluted with water, ethanolwas removed by destillation. The residue was alkalized with aqueoussodium hydroxid solution (30%) and extracted with diethylether. Thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo to yield 2.02 g of1-(4,4-difluorocyclohexyl)pyrazole as oil.

Analysis: HPLC-MS: R_(t)=0.46 min (method C), M+H=187

Step 5: Synthesis of 4-Bromo-1-(4,4-difluorocyclohexyl)pyrazole

To a solution of 2.0 g of 1-(4,4-difluorocyclohexyl)pyrazole in 5 mL DCMwas added 0.55 mL bromine at 0° C. and the mixture was stirred at roomtemperature for 15 min. The solvent was removed by destillation and theresidue taken up in DCM and washed with semi saturated brine. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated in vacuo to yield 2.81 g of4-bromo-1-(4,4-difluorocyclohexyl)pyrazole 3.12 as solid.

Analysis: HPLC-MS: R_(t)=0.60 min (method C), M+H=265/267

Synthesis of 4-Bromo-1-(difluoromethyl) imidazole 3.13 for Example 83

Into a mixture of 10.0 g of 4-bromo-1H-imidazole in 60 mL DMF was passed30 g chlorodifluoromethane under dry ice cooling, then 15.0 g potassiumcarbonate were added and the reaction mixture was heated to 110° C.overnight in a sealed tube (19 bar). Additional 30 gchlorodifluoromethane and 5 g potassium carbonate were added and thereaction mixture was heated to 110° C. overnight (9 bar). The reactionmixture was allowed to reach ambient temperature, then diluted withwater and extracted with ethyl acetate. The combined organic extractswere washed with saturated brine, dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by rpHPLC(SunfireC18, acetonitrile/water trifluoroacetic acid) to yield 3.07 g4-bromo-1-(difluoromethyl) imidazole.

Analysis: HPLC-MS: R_(t)=0.371 min (method J), M+H=197/199

The following bromides were commercially available:

-   3-Bromoimidazo[1,2-a]pyridine-6-carbonitrile 3.14 for Example 43,-   4-Bromo-1-(3,3,3-trifluoro-propyl)pyrazole 3.15 for Example 15, 76-   3-Bromo-1H-indazole-5-carbonitrile 3.16 for Example 16-   2-Bromo-5-fluoro-pyridine 3.17 for Example 41-   4-(4-Bromophenyl)-1-methyl-piperidine 3.18 for Example 42-   2-(4-Bromo-2-methyl-phenyl)-1,2-thiazolidine 1,1-dioxide 3.19 for    Example 71-   7-Bromo-2-methyl-3,4-dihydro-1H-isoquinoline 3.20 for Example 75-   4-Bromo-1-isopropoxy-2-methoxy-benzene 3.22 for Example 81-   5-Bromo-1-methyl-indazol-3-amine 3.23 for Example 36,-   2-(4-Bromophenyl)-1,2-thiazolidine 1,1-dioxide 3.24 for Example 33-   4-Bromo-1-(difluoromethyl)pyrazole 3.25 for Example 40-   4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 3.26 for Example 3-   1-[(4-Bromophenyl)methyl]-2-methyl-1H-imidazole 3.27 for Example 17    4.1.3. Synthesis of compounds of formula 4 (R¹—X) (Scheme 1 and 2)

Synthesis of Tributyl-[2-(difluoromethyl)thiazol-4-yl]stannane 4.1 forExample 35

To a mixture of 500 mg of 4-tributylstannylthiazole-2-carbaldehyde in 5mL DCM was slowly added 1.01 mL 2.7M [bis(2-methoxyethyl)amino]sulfurtrifluoride solution (in toluene) at 0° C., then the mixture was allowedto warm to ambient temperature and stirred for 2 h. The reaction mixturewas diluted with DCM and washed with water. The combined organic phaseswere dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (heptane/ethylacetate/methanol) to yield 440 mg (82% per HPLC)tributyl-[2-(difluoromethyl)thiazol-4-yl]stannane 4.1 as oil.

Analysis: HPLC-MS: R_(t)=2.72 min (method M), M+H=425

The following stannane was commercially available:

-   Tributyl(thiazol-4-yl)stannane 4.2 for Example 29

Synthesis of3-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3-benzazepine4.3 for Example 55

100 mg of 7-bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine, 127 mgbis-(pinacolato)-diboron, 20 mg1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II) and 123 mgpotassium acetate were suspended in 2 mL dioxane and the mixture stirredat 100° C. for 1.25 h. The mixture was diluted after cooling withdioxane, filtered through Celite, washed with dioxane and the solventwas evaporated in vacuo to yield 220 mg (92%, content 50%)3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3-benzazepine4.3 as solid, which was used in the next step without furtherpurification.

Analysis: HPLC-MS: R_(t)=0.45 min (method N), M+H=288

The following boronic esters were synthesized in analogy and were usedwithout further purification:

-   1-Methyl-4-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-cyclohexyl}-piperazin-2-one    4.4 starting from 3.2 (for Example 12). Reaction conditions: 4 h,    100° C. Yield: 81% (content 36%). Analysis: HPLC-MS: R_(t)=0.41 min    (method O), M+H=389-   2-Difluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine    4.5 starting from 3.3 (for Example 51). Reaction conditions: 45 min,    100° C. Yield: 82% (content 40%). Analysis: HPLC: R_(t)=0.25 min    (method N); MS: M+H=256-   N,N,1-Trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxamide    4.6 starting from 3.5 (for Example 56). Reaction conditions: 3 h,    100° C. Yield: 84% (content 50%). Analysis: HPLC-MS: R_(t)=0.69 min    (method N), M+H=329-   1-[(3S)-Tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.7 starting from 3.6 (for Example 70). Reaction conditions: 3 h,    100° C. Yield: 59% (content 50%). Analysis: HPLC-MS: R_(t)=0.49 min    (method N), M+H=265-   2-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-thiazolidine    1,1-dioxide 4.8 starting from 3.19 (for Example 71). Reaction    conditions: 3 h, 100° C. Yield: 86% (content 50%). Analysis:    HPLC-MS: R_(t)=0.64 min (method N), M+H=338-   1-[(3R)-Tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.9 starting from 3.7 (for Example 74). Reaction conditions: 5 h,    100° C. Yield: 43% (content 38%). Analysis: HPLC-MS: R₁=0.54 min    (method J), M+H=265-   2-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline    4.10 starting from 3.20 (for Example 75). Reaction conditions: 2 h,    100° C. Yield: 99% (content 43%). Analysis: HPLC-MS: R_(t)=0.41 min    (method J), M+H=274-   4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole    4.11 starting from 3.15 (for Example 76). Reaction conditions: 4 h,    100° C. Yield: 29% (content 25%). Analysis: HPLC-MS: R_(t)=0.61 min    (method J), M+H=291-   1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine    4.12 starting from 3.9 (for Example 80). Reaction conditions: 4 h,    100° C. Yield: 84% (content 50%). Analysis: HPLC-MS: R_(t)=0.47 min    (method J), M+H=302-   2-(4-Isopropoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane    4.13 starting from 3.22 (for Example 81). Reaction conditions: 3 h,    100° C. Yield: 87% (content 40%). Analysis: HPLC-MS: R_(t)=0.75 min    (method J), M+H=293-   2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-thiazolidine    1,1-dioxide 4.14 starting from 3.24 (for Example 33). Reaction    conditions: 2.5 h, 80° C., in DMF. Yield: 68% (content 95%).    Analysis: HPLC-MS: R_(t)=2.04 min (method K), M+H=324

The following examples were synthesized in analogy to the describedexample but using bis(triphenylphosphine)palladium(II) chloride (0.05eq.) instead of 1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II)as catalyst (see description above):

-   1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-amine    4.15 starting from 3.23 (for Example 36). Reaction conditions: 1 h,    95° C. Yield: 89% (content 85%). Analysis: HPLC-MS: R_(t)=1.76 min    (method K), M+H=274-   1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]piperazine    4.16 starting from 3.10 (for Example 32). Reaction conditions: 1.5    h, 95° C. Yield: 61% (content 95%). Analysis: HPLC-MS: R_(t)=1.66    min (method K), M+H=371-   1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.17 starting from 3.25 (for Example 40). Reaction conditions: 2.5    h, 95° C. Yield: 70% (content 95%). Analysis: HPLC-MS: R_(t)=1.97    min (method K), M+H=245-   4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]morpholine    4.18 starting from 3.11 (for Example 38). Reaction conditions: 1 h,    95° C. Yield: 99% (content 78%). Analysis: HPLC-MS: R_(t)=2.67 min    (method K), M+H=358

Synthesis of1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole4.19 for Examples 2,18

To a stirred mixture of 50 g of 4-bromo-1-tert-butyl-pyrazole 3.1 in 230mL THF was added dropwise 100 mL 2.5M N-butyllithium solution in hexaneunder argon atmosphere below −60° C., then the mixture was stirred atthis temperature for 5 min, before 52 mL2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were added dropwisebelow −60° C. The reaction mixture was allowed to reach ambienttemperature. The mixture was cooled with an ice bath and diluted withaqueous phosphate buffer solution and water and neutralized with 2Maqueous hydrochloric acid. The organic solvent was removed bydestillation and the residue was extracted with DCM. The combinedorganic extracts were washed with saturated brine, dried over sodiumsulfate, filtered and concentrated in vacuo to yield 44.26 g of1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole assolid.

Analysis: HPLC-MS: R_(t)=0.904 min (method F), M+H=251

Synthesis of5-Methyl-1-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole4.20 for Example 79

This intermediate was prepared from4-bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazole 3.8 according to thepreparation of1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole4.19.

Yield: 94% of 4.20

Analysis: HPLC-MS: R_(t)=0.58 min (method J), M+H=293

Synthesis of1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine4.21 for Example 49

A mixture of 250 mg4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]piperidine-1-carboxylicacid tert-butyl ester 4.51 and 0.5 mL trifluoroacetic acid in 2 mL DCMwas stirred at room temperature for 1 h. The solvent was removed bydestillation and the residue taken up in 10 mL DCM, followed by additionof 494 μL formaldehyde (aqueous 37%). The reaction mixture was stirredat room temperature for 1 h, before 421 mg sodium triacetoxyborhydridewere added. The resulting mixture was stirred at room temperature for 30min, diluted with saturated aqueous sodium bicarbonate solution andextracted with DCM. The combined organic phases were dried over sodiumsulfate, filtered and concentrated in vacuo to yield 99 mg of1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine4.21 as solid.

Analysis: HPLC-MS: R_(t)=1.25 min (method K), M+H=292

The following boronic acids, boronic esters and BF₃ borates werecommercially available:

-   (3,4-Dimethoxyphenyl)boronic acid 4.22 for Example 1-   2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine    4.23 for Example 50-   2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4.24    for Examples 8, 73-   (3,4,5-Trimethoxyphenyl)boronic acid 4.25 for Example 52-   tert-Butyl-5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate    4.26 for Example 53-   1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.27 for Example 57-   1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.28    for Example 58-   [6-(Trifluoromethyl)-3-pyridyl]boronic acid 4.29 for Examples 4, 61-   (1-Methylindazol-5-yl)boronic acid 4.30 for Example 62-   1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.31 for Example 63-   1-Tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.32 for Examples 47, 64-   1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.33 for Example 65-   4-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine    4.34 for Example 66-   1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine    4.35 for Examples 26, 67-   1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.36 for Example 68-   1,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.37 for Example 69-   (1-Methylindazol-6-yl)boronic acid 4.38 for Example 72-   7-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole    4.39 for Examples 48, 77-   1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.40 for Example 78-   tert-Butyl    4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate    4.41 for Examples 9, 45, 82-   Potassium 5-methyl-2-thiophenetrifluoroborate 4.42 for Example 54-   Potassium 6-methoxy-3-pyridyltrifluoroborate 4.43 for Example 59-   Potassium 4-(trifluoromethyl)phenyltrifluoroborate 4.44 for Example    60-   5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine    4.45-   (4-Morpholinophenyl)boronic acid 4.46 for Example 22-   (1-Methylindazol-5-yl)boronic acid 4.47 for Examples 28-   2-Isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine    4.48 for Example 27-   1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole    4.49 for Example 14-   1-Cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazole    4.50 for Example 7-   4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]piperidine-1-carboxylic    acid tert-butyl ester 4.51 for Example 49    4.1.4. Synthesis of Heterocyclic 5 and 10 from Scheme 1 and 2

Synthesis of 4,6-Dichloro-2-methyl-pyrazolo[4,3-c]pyridine 5.1 forExamples 1-3, 7-13, 17, 50-83

To a mixture of 9.5 g trimethyloxonium tetrafluoroborate in 300 mL DCMwas added 10.0 g of 4,6-dichloro-3aH-pyrazolo[4,3-c]pyridine(commercially available from Sphinx Scientific Laboratory Corporation)under argon atmosphere. The reaction mixture was stirred at roomtemperature overnight. Additional 2.7 g trimethyl-oxoniumtetrafluoroborate and 2.0 mL ethyldiisopropylamine (DIPEA) were addedand the reaction mixture was stirred at room temperature overnight. Thereaction mixture was diluted with water, filtered and the organic phasewas concentrated in vacuo. The crude material was taken up in semisaturated aqueous sodium bicarbonate solution. The precipitate wasfiltered off, washed with water and dried to yield 8.2 g of4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine 5.1 as solid.

Analysis: HPLC-MS: R_(t)=0.45 min (method C), M+H=202/204

Synthesis of 6-Bromo-2-methyl-indazol-4-ol 10.2 for Examples 14-16, 18,22, 26-29, 32, 33, 35, 36, 38, 40-43, 45, 47-49 Step 1: Synthesis of6-Bromo-4-methoxy-2-methyl-indazole

To a solution of 5.0 g of 6-bromo-4-methoxy-1H-indazole in 50 mL1,4-dioxane was added 4.23 g trimethyloxonium tetrafluoroborate at roomtemperature. The reaction mixture was stirred at 40° C. for 3 h and leftstanding overnight. The reaction mixture was poured into water. Theprecipitate was filtered off, washed with water and dried to yield 4.26g of 6-bromo-4-methoxy-2-methyl-indazole as solid.

Analysis: HPLC-MS: R_(t)=1.78 min (method K), M+H=241/243

Step 2: Synthesis of 6-Bromo-2-methyl-indazol-4-ol 10.2

To a suspension of 4.26 g of 6-bromo-4-methoxy-2-methyl-indazole in 42.6mL DCM was added 53.06 mL boron tribromide solution (1M in DCM) at 0° C.The reaction mixture was allowed to reach ambient temperature andstirred for 3 days. Additional 10 mL boron tribromide solution (1M inDCM) was added and the reaction mixture was stirred at room temperaturefor 8 h. The mixture was poured into water. The precipitate was filteredoff and triturated with acetonitrile to yield 2.8 g of6-bromo-2-methyl-indazol-4-ol 10.2 as solid. The acetonitrile filtratewas combined with the DCM layer and concentrated in vacuo. The residuewas triturated with acetonitrile to yield 1.08 g of6-bromo-2-methyl-indazol-4-ol 10.2 as solid. The two solids werecombined to yield 3.88 g of 6-bromo-2-methyl-indazol-4-ol 10.2 as solid.

Analysis: HPLC-MS: R_(t)=1.49 min (method K), M+H=227/229

4.2. Synthesis of Intermediates 6, 7, 8 and 11 from Scheme 1 and 2

Synthesis of(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one(7) for Examples 1-3, 7-13, 17, 50-83 Step 1: Synthesis of(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

To a mixture of 20.0 g of 4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine5.1 and 30.1 g(R)-4-[(R)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.1 in 1 L dioxane was added 4.51 g NaH in mineral oil (60%). Theresulting mixture was stirred at 100° C. for 15 h. The solvent wasremoved by destillation to ⅓. The residue was taken up in DCM und washedwith saturated ammonium chloride solution and water. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo to yield 44.8 g (88% per HPLC) of(R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-oneas solid.

Analysis: HPLC-MS: R_(t)=0.65 min (method J), M+H=429

Alternatively, 6.1 can be synthesized as following:

A solution of 20.0 g of 4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine5.1 and 25.4 g(R)-4-[(R)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.1 in 250 mL dioxane was added to a slurry of 9.6 g NaH in mineral oil(60%) in 50 mL of dioxane at 20° C. The resulting mixture was stirred at40° C. for 5.5 h. The mixture was cooled to ambient temperature andquenched by the slow addition of 36 mL of 4M HCl in dioxane. Thereaction mixture was diluted with 200 mL of isopropyl acetate and water(100 mL). The layers were separated, and the aqueous portion wasextracted with twice with 100 mL of isopropyl acetate. The organicportions were assayed to show 40.78 g of(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-onein a solution mass of 796.3 g for a 99% yield. Purification of 6.1 canbe conducted by concentration of a crude isopropyl acetate solution of50 g 6.1 in vacuo to 200 mL wherein solids crystallized. 500 mL ofheptane was slowly charged to the slurry at 20° C. and the mixture wasagitated for 2 h. The solids were collected by filtration, washed withheptane, and dried at 30° C. 46.9 g of 6.1 was isolated as a beige solidin 92% recovery.

Step 2: Synthesis of(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one7.1

A mixture of 1.0 g of(R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one6.1 and 1 mL anisole in 5 mL trifluoroacetic acid (TFA) was stirred at80° C. for 17 h. The solvent was removed by destillation. The residuewas taken up in DCM and washed with saturated aqueous sodium bicarbonatesolution. The combined organic phases were concentrated in vacuo and theresidue was triturated with diethyl ether. The precipitate was filteredoff and dried to yield 0.37 g of(R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-pyrrolidin-2-one7.1 as solid.

Analysis: HPLC-MS: R_(t)=0.47 min (method J), M+H=295

Synthesis of(4R)-4-[(1R)-1-(6-Bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one(7.5 for Examples 14-16, 18, 22, 26-29, 32, 33, 35, 36, 38, 40-43, 45,47-49 Step 1: Synthesis of(4R)-4-[(1R)-1-(6-Bromo-2-methyl-indazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

To a mixture of 1.46 g 6-bromo-2-methyl-indazol-4-ol 10.2, 1.86 g(R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.2 and 5.06 g triphenylphosphine in 36.5 mL THF was added 4.44 gdi-tert-butyl azodicarboxylate (DBAD) over 30 min. The resulting mixturewas stirred at room temperature for 18 h. The solvent was evaporated andthe residue triturated with TBME. The precipitate was filtered off andwashed with TBME. The filtrate was concentrated in vacuo and theresulting residue was purified by flash chromatography (heptane/ethylacetate/methanol) to yield 2.36 g (54% per HPLC) of(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one6.5 as solid.

Analysis: HPLC-MS: R_(t)=2.00 min (method K), M+H=472/474

Step 2: Synthesis of(4R)-4-[(1R)-1-(6-Bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one7.5

A mixture of 583 mg (63% per HPLC) of(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl) ethyl] pyrrolidin-2-one 6.5 in 10mL TFA was stirred at 70° C. for 18 h. The solvent was removed bydestillation. The residue was taken up in DCM, poured into saturatedaqueous sodium bicarbonate solution and extracted. The combined organicphases were dried over sodium sulfate, filtered and concentrated invacuo. The crude material was purified by flash chromatography(heptane/ethyl acetate/methanol) to yield 321 mg (84% per HPLC) of(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl) oxyethyl]pyrrolidin-2-one7.5.

Analysis: HPLC-MS: R_(t)=1.63 min (method K), M+H=338/340

4.1.6. Synthesis of Boronic Acids and Boronic Esters 11 from Scheme 1and 2

Synthesis of[2-Methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronicacid 11.1 for Examples 3, 10, 13, 17, 83

400 mg of(R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-pyrrolidin-2-one7.1, 620 mg bis-(pinacolato)-diboron, 122 mg 1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II) and 360 mg potassium acetate weresuspended in 4 mL dioxane and the mixture stirred at 100° C. for 1 h.The mixture was diluted with dioxane, filtered through Celite, washedwith dioxane and the solvent was evaporated in vacuo to yield 1.09 g(crude)[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronic acid 11.1 as oil, which was used in the next stepwithout further purification.

Analysis: HPLC-MS: R_(t)=0.26 min (method S), M+H=305

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one11.3 for Examples 15, 16, 41, 42, 43

500 mg of(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one7.5, 563 mg bis-(pinacolato)-diboron, 52 mgbis(triphenylphosphine)palladium(II) chloride and 435 mg potassiumacetate were suspended in 5 mL dioxane and the resulting mixture wasstirred at 95° C. for 1 h. The reaction mixture was allowed to reachambient temperature, diluted with water and extracted with DCM. Thecombined organic phases were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(heptane/ethyl acetate/methanol) to yield 505 mg (78% per HPLC) of(4R)-4-[(1R)-1-[2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one11.3.

Analysis: HPLC-MS: R_(t)=1.76 min (method K), M+H=387

4.3 Synthesis of the Patent Examples of Formula 1

Synthesis of(4R)-4-[(1R)-1-[6-(3,4-Dimethoxyphenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 1)

A mixture of 150 mg(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one7.1, 139 mg (3,4-dimethoxyphenyl)boronic acid 4.22, 17.9 mgbis(triphenylphosphine)palladium(II) chloride and 764 μL 2M aqueoussodium carbonat solution in 1.7 mL DMF was stirred at 90° C. for 20 h.The reaction mixture was allowed to reach ambient temperature andpurified by rpHPLC to yield after lyophilisation 42 mg of Example 1.

Analysis: HPLC-MS: R_(t)=3.72 min (method T), M+H=397

Synthesis of(4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 2) Step 1: Synthesis of(4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

To a mixture of 1.0 g(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one6.1, 790 mg 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)4.19 and 170 mg 1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II) (complex with DCM (1:1)) in 6 mL dioxanewas added 5.0 mL 2M aqueous sodium carbonat solution. The resultingmixture was stirred in a sealed tube at 140° C. for 1h. The reactionmixture was poured into DCM. The precipitate was filtered off. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by flash chromatography (DCM/methanol=1/0→9/1) to yield 1.0 g(50% per NMR) of(4R)-4-[(1R)-1-[6-(1-tert-butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one8.1 as oil.

Analysis: HPLC-MS: R_(t)=0.63 min (method C), M+H=517

Step 2: Synthesis of(4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 2)

A mixture of 3.90 g (36% per HPLC) of(4R)-4-[(1R)-1-[6-(1-tert-butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one8.1 in 25 mL TFA was stirred at 80° C. for 3h. The reaction mixture waspurified by rpHPLC (SunfireC18, acetonitrile/water, TFA and XbridgeC18,acetonitrile/water, ammonia) and the desired fractions were lyophilized.The residue was triturated with TBME and a small amount of acetone. Thesolvent was removed by destillation and the residue was dried to yield410 mg of Example 2 as solid.

Analysis: HPLC-MS: R_(t)=0.52 min (method C), M+H=383

Alternatively, 8.1 can be synthesized as following:

Synthesis of Ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate

A solution of ethyl 2-cyano-3-ethoxyacrylate (5.0 g, 30 mmol) inanhydrous THF (10 mL) was charged dropwise to a mixture of sodiumethoxide (4.02 g, 59 mmol) and methylhydrazine (1.36 g, 30 mmol) inabsolute ethanol (10 mL) at 0° C. under nitrogen. After aging theagitated mixture for 90 min, a solution of anhydrous hydrochloric acid(3.22 M in CPME, 28 mL, 90 mmol) was charged to the reaction dropwise.The reaction was then concentrated in vacuo to a solid, diluted withisopropyl acetate (20 mL) and concentrated to a solid. The crude pastewas suspended in hot isopropyl acetate (75 mL) and filtered hot. Thefiltrate was concentrated in vacuo to approximately 15 mL wherein asolid crystallized upon cooling to ambient temperature. The mixture wasdiluted by the dropwise addition of heptane (30 mL). The mixture wasagitated for 1h at ambient temperature. Ethyl3-amino-1-methyl-1H-pyrazole-4-carboxylate was isolated by filtration,washed with heptane and dried under vacuum to provide 3.7 g as ayellow-orange solid in 74% yield. ¹H NMR (500 MHz, DMSO-d⁶) δ=7.87 (s,1H), 5.3 (bs, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.60 (s, 3H), 1.23 (t, J=7.2Hz, 3H).

Synthesis of Ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate

Isoamyl nitrite (420 mg, 3.6 mmol) was charged dropwise to an agitatedmixture of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (400 mg, 2.4mmol) and copper (II) bromide (660 mg, 3.0 mmol) in anhydrousacetonitrile (10 mL) at ambient temperature. The reaction was agitatedfor one hour; at which point, the reaction was diluted with isopropylacetate (100 mL). The mixture was washed with water (100 mL) andconcentrated to an oily residue. Purification by silica gelchromatography with methyl t-butyl ether and hexanes provided ethyl3-bromo-1-methyl-1H-pyrazole-4-carboxylate (350 mg) as a white solid in64% yield. ¹H NMR (500 MHz, CDCl₃) δ=7.83 (s, 1H), 4.30 (q, J=7.1 Hz,2H), 3.90 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).

Synthesis of 3-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid

An aqueous solution of sodium hydroxide (2 M, 10 mL, 20 mmol) wascharged to a mixture of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate(2.0 g, 8.6 mmol) in ethanol (20 mL) at ambient temperature. Thereaction was agitated at 50° C. for 1h; at which point, the reaction wascooled to ambient temperature. An aqueous solution of hydrochloric acid(3 M, 6.7 mL, 20 mmol) was charged dropwise to the reaction to inducecrystallization. The solids of 3-bromo-1-methyl-1H-pyrazole-4-carboxylicacid were collected by filtration, washed with water followed byheptane, and dried to afford 1.4 g as a white solid in 79% yield. ¹H NMR(400 MHz, DMSO-d⁶) δ=12.59 (s, 1H), 8.27 (s, 1H), 3.85 (s, 3H).

Synthesis of 1-(1-(tert-Butyl)-1H-pyrazol-4-yl)ethan-1-one

Isopropyl magnesium chloride lithium chloride complex (1.3 M in THF,28.4 mL, 37 mmol) was charged to a solution of4-bromo-1-(tert-butyl)-1H-pyrazole (5.0 g, 25 mmol) in anhydrous THF (25mL) under argon at ambient temperature. Anhydrous dioxane (3.3 g, 37mmol) was charged to the reaction, and the reaction was agitated at 45°C. for 4 h. The resulting mixture was cooled to ambient temperature andcharged to an anhydrous solution of acetic anhydride (7.5 g, 73 mmol) inTHF (25 mL) at −20° C. The resulting mixture was warmed to ambienttemperature and concentrated to a residue. The mixture was dissolved inmethyl t-butyl ether (50 mL) and washed with water (25 mL). The organicportion was concentrated to provide crude1-(1-(tert-butyl)-1H-pyrazol-4-yl)ethan-1-one as an oil (7.6 g, 36 wt %)and 67% yield. Crystallization in a mixture of methyl t-butyl ether andheptane provided analytically pure material. ¹H NMR (500 MHz, CDCl₃)δ=7.96 (s, 1H), 7.86 (s, 1H), 2.37 (s, 3H), 1.55 (s, 9H).

Synthesis of6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-one

A mixture of lithium tert-butoxide (0.970 g, 12 mmol), palladium (II)acetate (27 mg, 0.12 mmol), anddi-tert-butyl(2,4,6-trisopropylbiphenyl-2-yl)phosphine (77 mg, 18 mmol)in anhydrous and degassed 1,4 dioxane (4 mL) under argon was agitated atambient temperature for 15 minutes. The mixture was heated to 90° C.,and agitated at this temperature for 5 minutes. A solution of3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.4 mmol) and1-(1-(tert-Butyl)-1H-pyrazol-4-yl)ethan-1-one (490 mg, 2.9 mmol) inanhydrous and degassed 1,4-dioxane (7 mL) under argon was charged to thecatalysts base slurry at 90° C. dropwise over 50 minutes. The reactionwas agitated at 90° C. for 30 minutes. The reaction was cooled toambient temperature and quenched by the addition of trifluoroacetic acid(5 mL). The reaction was concentrated to an oily solid. The mixture wassuspended in a mixture of acetonitrile (20 mL) and trifluoroacetic acid(20 mL). The mixture was agitated at 75° C. for 14 h then concentratedto an oily solid. The mixture was suspended in isopropyl acetate (70 mL)and washed twice with water (40 mL). The organic portion wasconcentrated to a solid. Purification by silica gel chromatography withethyl acetate and hexanes provided6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-oneas an orange solid (650 mg) in 98% yield. ¹H NMR (500 MHz, CDCl₃) δ=8.06(s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 6.68 (s, 1H), 4.04 (s, 3H), 1.60(s, 9H).

Synthesis of6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

A mixture of6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-one(980 mg, 3.6 mmol) and ammonium acetate (1.11 g, 14 mmol) in anhydrousDMSO (4 mL) was agitated at 110° C. for 4 h; at which point, additionalammonium acetate (1.11 g, 3.6 mmol) was charged to the reaction. Afteragitation for another 4 h at 110° C., the reaction was cooled to ambienttemperature and diluted with water (20 mL). The solids of6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-onewere isolated by filtration, washed with water, and dried to provide 880mg for an 90% yield. ¹H NMR (500 MHz, DMSO-d⁶) δ=10.59 (s, 1H), 8.54 (s,1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.73 (s, 1H), 3.99 (s, 3H), 1.53 (s,9H).

Synthesis of6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine

Phosphorous (V) oxychloride (848 mg, 5.53 mmol) was charged to a mixtureof6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(500 mg, 1.84 mmol) in anhydrous acetonitrile (5 mL) under argon. Thereaction was agitated at 75-80° C. for 3 h; at which point, the reactionwas cooled to ambient temperature. The reaction slowly poured into asaturated sodium bicarbonate aqueous solution (45 mL). The mixture wasagitated for 20 min and concentrated in vacuo to remove the acetonitrilesolvent. The resulting aqueous slurry was diluted with isopropyl acetate(50 mL) and washed with water (2×20 mL). The organic portion wasconcentrated to an oil which solidified upon standing to provide6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridineas a yellow solid (690 mg, 73 wt %) in 92% yield. Analytically purematerial was obtained by crystallization in n-propanol and heptane. ¹HNMR (500 MHz, CDCl₃) δ=8.08 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.52(s, 1H), 4.20 (s, 3H), 1.62 (s, 9H).

Synthesis of(R)-4-((R)-1-((6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one(8.1)

A mixture of(R)-4-((R)-1-hydroxyethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one(173 mg, 0.66 mmol),6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine(190 mg, 66 mmol) and sodium hydride (60 wt %, 66 mg, 1.6 mmol) inanhydrous 1,4 dioxane (3 mL) was agitated under argon at 50-70° C. for18 h. The reaction mixture was cooled to ambient temperature andquenched by the slow addition of a hydrogen chloride solution (4 M in1,4 dioxane, 0.245 mL, 0.98 mmol). The reaction was diluted withisopropyl acetate (20 mL) and water (20 mL). The layers were separated,and the aqueous portion was extracted twice with isopropyl acetate (20ml). The combined organic layers were concentrated to an oil.Purification by silica gel chromatography with methanol and methyltert-butyl ether provided(R)-4-((R)-1-((6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one(185 mg) as a white foam in 55% yield. ¹H NMR (500 MHz, CDCl₃) δ=7.94(s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 7.10 (d, J=8.8 Hz,2H), 6.57 (d, J=8.7 Hz, 2H), 5.48 (dddd, J=4.8, 6.1, 6.1, 6.1 Hz, 1H),5.43 (q, J=7.0 Hz, 1H), 4.13 (s, 3H), 3.66 (s, 3H), 3.47 (t, J=9.0 Hz,1H), 2.96 (dd, J=5.1, 9.8 Hz, 1H), 2.74-2.66 (m, 1H), 2.66-2.57 (m, 2H),1.64 (s, 9H), 1.48 (d, J=7.1 Hz, 3H), 1.33 (d, J=6.2 Hz, 3H).

Synthesis of(4R)-4-[(1R)-1-[6-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 3)

To a mixture of 50 mg[2-Methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronicacid 11.1, 46.2 mg 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 3.26and 20 mg palladium-X-phos was added to 3 mL dioxane and 65 μL 5Maqueous sodium carbonat solution. The resulting mixture was heated at110° C. for 14h. The mixture was cooled to ambient temperature aundpurified via rpHPLC. The combined organic phases were lyophilized toprovide example 3 in 21 mg.

Analysis: HPLC-MS: R_(t)=0.86 min (method Z1), M+H=411

Example 17 was synthesized in analogous manner to Example 3 using1-[(4-bromophenyl)methyl]-2-methyl-1H-imidazole 3.27.

Analysis: HPLC-MS: R_(t)=0.73 min (method Z1), M+H=431

Synthesis of(4R)-4-[(1R)-1-[6-(4-Hydroxy-3-methoxy-phenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 8)

To a mixture of 100 mg(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one7.1, 110 mg2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4.24 and37 mg 1,1′-bis(diphenylphospino)ferrocene-dichloropalladium(II) (complexwith DCM (1:1)) in 1 mL dioxane and 0.5 mL methanol was added 400 μL 2Maqueous sodium carbonat solution. The reaction mixture was stirred at140° C. for 15 min under microwave irradiation. The reaction mixture wasfiltered through rpSiO₂, washed with methanol and purified by rpHPLC toyield after lyophilisation 80 mg (yield: 68%) of Example 8 as solid.

Analysis: HPLC-MS: R_(t)=0.47 min (method S), M+H=383

The following Examples were synthesized in analogous manner to Example8.

Boronic acid/ester or BF₃ borates (corresponding to Example formula 4)Yield Analysis Example 7 1-Cyclohexyl-4- 50 mg HPLC-MS:(R)-4-((R)-1-(6-(1-cyclohexyl- (4,4,5,5-tetramethyl- (47%) R_(t) = 0.72min 1H-pyrazol-4-yl)-2-methyl-2H- 1,3,2-dioxoborolan- (method U),pyrazolo[4,3-c]pyridin-4- 2-yl)-1H-pyrazole M + H = 409yloxy)ethyl)pyrrolidin-2-one 4.50 Example 53 tert-butyl 5-methoxy- 51 mgHPLC-MS: (4R)-4-[(1R)-1-[6-(5-methoxy- 3-(4,4,5,5- (51%) R_(t) = 0.64min 1H-indol-3-yl)-2-methyl- tetramethyl-1,3,2- (method U),pyrazolo[4,3-c]pyridin-4- dioxaborolan-2- M + H = 406yl]oxyethyl]pyrrolidin-2-one yl)indole-1-carboxylate ¹H NMR (DMSO, 4.26400 MHz) δ = 1.42 (3H, d), 2.20-2.36 (2H, m), 2.75-2.89 (1H, m), 3.12(dd, 1H), 3.40 (1H, t), 3.82 (3H, s), 4.12 (3H, s), 5.58-5.68 (1H, m),6.79 (1H, d), 7.32 (1H, d), 7.41 (1H, s), 7.53 (1H, s), 7.80 (1H, s),7.96 (1H, s), 8.42 (s, 1H), 11.2 (1H, s). Example 54 potassium 5-methyl-36 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-(5- 2-thiophene-tri- (67%)R_(t) = 0.68 min methyl-2-thienyl)pyrazolo-[4,3- fluoroborate 4.42(method V), c]pyridin-4-yl]oxyethyl]- M + H = 357 pyrrolidin-2-oneExample 55 3-methyl-7-(4,4,5,5- 29 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(3- tetramethyl-1,3,2- (46%) R_(t) = 0.62 minmethyl-1,2,4,5-tetrahydro-3- dioxaborolan-2-yl)- (method V),benzazepin-7-yl)pyrazolo-[4,3- 1,2,4,5-tetrahydro-3- M + H = 420c]pyridin-4-yl]oxyethyl]- benzazepine 4.3 pyrrolidin-2-one Example 56N,N,1-trimethyl-6- 34 mg HPLC-MS: N,N,1-trimethyl-6-[2-methyl-4-(4,4,5,5-tetramethyl- (49%) R_(t) = 0.59 min[(1R)-1-[(3R)-5-oxopyrrol-idin- 1,3,2-dioxaborolan- (method V),3-yl]ethoxy]pyrazolo[4,3- 2-yl)indole-2- M + H = 461c]pyridin-6-yl]indole-2- carboxamide 4.6 carboxamide Example 59potassium 6- 37 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(6-methoxy-methoxy-3-pyridyl- (66%) R_(t) = 0.57 min 3-pyridyl)-2-methyl-pyrazolo-trifluoroborate (method V), [4,3-c]pyridin-4-yl]oxyethyl]- 4.44 M + H =368 pyrrolidin-2-one Example 60 potassium 4- 19 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-[4- (trifluoromethyl)phenyltrifluoroborate(31%) R_(t) = 0.75 min (trifluoromethyl)phenyl]- 4.44 (method V),pyrazolo[4,3-c]pyridin-4-yl]- M + H = 405 oxyethyl]pyrrolidin-2-oneExample 64 1-tetrahydropyran-4- 48 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(1- yl-4-(4,4,5,5- (76%) R_(t) = 0.57 mintetrahydropyran-4-yl-pyrazol- tetramethyl-1,3,2- (method W),4-yl)pyrazolo[4,3-c]pyridin-4- dioxaborolan-2- M + H = 411yl]oxyethyl]-pyrrolidin-2-one yl)pyrazole 4.32 Example 65 1-isopropyl-4-31 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1-iso- (4,4,5,5-tetramethyl- (55%)R_(t) = 0.61 min propylpyrazol-4-yl)-2-methyl- 1,3,2-dioxaborolan-(method W), pyrazolo[4,3-c]pyridin-4-yl]- 2-yl)pyrazole 4.33 M + H = 369oxyethyl]pyrrolidin-2-one ¹H NMR (DMSO, 400 MHz) δ = 1.35 (3H, d), 1.46(6H, d), 2.20-2.32 (2H, m), 2.72-2.83 (1H, m), 3.12 (m, 1H), 3.38 (1H,t), 4.10 (3H, s), 4.48-4.59 (1H, m), 5.50-5.60 (1H, m), 7.30 (1H, s),7.51 (1H, s), 7.99 (1H, s), 8.21 (1H, s), 8.41 (s, 1H). Example 664-[5-(4,4,5,5- 49 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-(6-tetramethyl-1,3,2- (76%) R_(t) = 0.46 min morpholino-3-pyridyl)-dioxaborolan-2-yl)-2- (method W), pyrazolo[4,3-c]pyridin-4-pyridyl]-morpholine M + H = 423 yl]oxyethyl]pyrrolidin-2-one 4.34Example 67 1-methyl-4-[4- 20 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-[4-(4,4,5,5-tetramethyl- (24%) R_(t) = 0.46 min (4-methylpiperazin-1-1,3,2-dioxaborolan- (method W), yl)phenyl]pyrazolo[4,3- 2-yl)phenyl]-M + H = 435 c]pyridin-4-yl]oxyethyl]- piperazine 4.35 pyrrolidin-2-oneExample 68 1,3-dimethyl-4- 36 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1,3-(4,4,5,5-tetramethyl- (67%) R_(t) = 0.52 min dimethylpyrazol-4-yl)-2-1,3,2-dioxaborolan- (method W), methyl-pyrazolo[4,3-c]pyridin-2-yl)pyrazole 4.36 M + H = 355 4-yl]oxyethyl]pyrrolidin-2-one Example 691,5-dimethyl-4- 39 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1,5-dimethylpyrazol-(4,4,5,5-tetramethyl- (72%) R_(t) = 0.52 min 4-yl)-2-methyl- 1,3,2-dioxa borolan- (method W), pyrazolo[4,3-c]pyridin-4- 2-yl)pyrazole 4.37M + H = 355 yl]oxyethyl]pyrrolidin-2-one Example 70 1-[(3S)- 14 mgHPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-[1- tetrahydrofuran-3- (23%) R_(t) =0.55 min [(3S)-tetrahydrofuran-3- yl]-4-(4,4,5,5- (method W),yl]pyrazol-4-yl]pyrazolo[4,3- tetramethyl-1,3,2- M + H = 397c]pyridin-4-yl]oxyethyl]- dioxaborolan-2- pyrrolidin-2-one yl)pyrazole4.7 Example 71 2-[2-methyl-4- 42 mg HPLC-MS: (4R)-4-[(1R)-1-[6-[4-(1,1-(4,4,5,5-tetramethyl- (58%) R_(t) = 0.66 mindioxo-1,2-thiazolidin-2-yl)-3- 1,3,2-dioxaborolan- (method W),methyl-phenyl]-2-methyl- 2-yl)phenyl]-1,2- M + H = 470pyrazolo[4,3-c]pyridin-4- thiazolidine 1,1- yl]oxyethyl]pyrrolidin-2-onedioxide 4.8 Example 72 (1-methylindazol-6- 34 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(1- yl)boronic acid 4.38 (57%) R_(t) = 0.67min methylindazol-6-yl)pyrazolo[4, (method W), 3-c]pyridin-4- M + H =391 yl]oxyethyl]pyrrolidin-2-one Example 74 1-[(3R)-tetrahydrofuran- 13mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-[1- 3-yl]-4- (25%) R_(t) = 0.47min [(3R)-tetrahydrofuran-3- (4,4,5,5-tetramethyl- (method V),yl]pyrazol-4-yl]pyrazolo[4,3- 1,3,2-dioxaborolan- M + H = 397c]pyridin-4-yl]oxyethyl]- 2-yl)pyrazole 4.9 pyrrolidin-2-one Example 752-methyl-7-(4,4,5,5- 18 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-(2-tetramethyl-1,3,2- (23%) R_(t) = 0.61 min methyl-3,4-dihydro-1H-dioxaborolan-2-yl)- (method V), isoquinolin-7-yl)pyrazolo[4,3-3,4-dihydro-1H- M + H = 406 c]pyridin-4-yl]oxyethyl]- isoquinoline 4.10pyrrolidin-2-one Example 76 4-(4,4,5,5- 17 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-[1- tetramethyl-1,3,2- (25%) R_(t) = 0.44 min(3,3,3-trifluoropropyl)-pyrazol- dioxaborolan-2-yl)-1- (method X),4-yl]pyrazolo[4,3-c]pyridin-4- (3,3,3-trifluoro- M + H = 423yl]oxyethyl]-pyrrolidin-2-one propyl)pyrazole 4.11 Example 777-chloro-2-(4,4,5,5- 27 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(7-chloro-1H-tetramethyl-1,3,2- (32%) R_(t) = 0.59 min indol-2-yl)-2-methyl-dioxaborolan-2-yl)- (method X), pyrazolo[4,3-c]pyridin-4- 1H-indole 4.39M + H = 410 yl]oxyethyl]pyrrolidin-2-on Example 78 1-cyclopropyl-4- 40mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1- (4,4,5,5-tetramethyl- (51%) R_(t) =0.40 min cyclopropylpyrazol-4-yl)-2- 1,3,2-dioxaborolan- (method X),methyl-pyrazolo[4,3-c]pyridin- 2-yl)pyrazole 4.40 M + H = 3674-yl]oxyethyl]pyrrolidin-2-one Example 79 5-methyl-1- 26 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(3- tetrahydropyran-4-yl- (28%) R_(t) = 0.39min methyl-1-tetrahydropyran-4-yl- 4-(4,4,5,5- (method Y),pyrazol-4-yl)pyrazolo-[4,3- tetramethyl-1,3,2- M + H = 425c]pyridin-4-yl]oxyethyl]- dioxaborolan-2- pyrrolidin-2-one yl)pyrazole4.20 Example 80 1-methyl-4-[4- 24 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-[4- (4,4,5,5-tetramethyl- (32%) R_(t) = 0.50min (1-methyl-4-piperidyl)- 1,3,2-dioxaborolan- (method Y),phenyl]pyrazolo[4,3-c]pyridin- 2-yl)phenyl]- M + H = 4344-yl]oxyethyl]pyrrolidin-2-one piperidine 4.12 Example 812-(4-isopropoxy-3- 35 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(4- methoxy-phenyl)-(35%) R_(t) = 0.51 min isopropoxy-3-methoxy- 4,4,5,5-tetramethyl-(method Y), phenyl)-2-methyl-pyrazolo- 1,3,2-dioxaborolane M + H = 425[4,3-c]pyridin-4-yl]oxyethyl]- 4.13 pyrrolidin-2-one

The following examples were synthesized in analogy to Example 8 butusing different reaction solvents:

Boronic acid/ester (corresponding to Yield Example formula 4) SolventAnalysis Example 11 11 mg HPLC-MS: (4S)-4-[(1R)-1-[2-methyl-6-[2-  (9%)R_(t) = 0.463 min methyl-4-[(1R)-1-[(3R)-5- dioxane (method C)oxopyrrolidin-3-yl]ethoxy]- M + H = 519 pyrazolo[4,3-c]pyridin-6-yl]pyrazolo[4,3-c]pyridin-4- yl]oxyethyl]pyrrolidin-2-one Example 12trans 1-methyl-4-{4- 13 mg HPLC-MS: 1-methyl-4-[4-[4-[2-methyl-4-[4-(4,4,5,5- (10%) R_(t) = 0.423 min [(1R)-1-[(3R)-5-oxopyrrolidin-tetramethyl-1,3,2- dioxane (method C) 3-yl]ethoxy]pyrazolo[4,3-dioxaborolan-2-yl)- M + H = 521 c]pyridin-6-yl]pyrazol-1-yl]-pyrazol-1-yl]- cyclohexyl]piperazin-2-one cyclohexyl}-piperazin- 2-one4.4 Example 62 (1-methylindazol-5- 33 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(1- yl)boronic acid 4.30 (50%) R_(t) = 0.55min methylindazol-5- DMA (method V), yl)pyrazolo[4,3-c]pyridin-4- M + H= 391 yl]oxyethyl]pyrrolidin-2-one ¹H NMR (DMSO, 400 MHz) δ = 1.42 (3H,d), 2.20-2.38 (2H, m), 2.75-2.88 (1H, m), 3.18 (dd, 1H), 3.40 (1H, t),4.08 (3H, s), 4.13 (3H, s), 5.59-5.68 (1H, m), 7.53 (1H, s), 7.65 (1H,s), 7.70 (1H, d), 7.80 (1H, s), 8.12 (1H, s), 8.16 (1H, d).

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 9) Step 1: Synthesis of tert-Butyl4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate

To a mixture of 100 mg(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one7.1, 170 mg tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate4.41 and 37 mg 1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II)(complex with DCM (1:1)) in 1 mL dioxane and 0.5 mL methanol was added400 μL 2M aqueous sodium carbonat solution. The reaction mixture wasstirred at 140° C. for 15 min under microwave irradiation. The reactionmixture was filtered through rpSiO₂, washed with methanol and purifiedby rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to yield afterlyophilisation 90 mg (80% per NMR) of tert-butyl4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo-[4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylateas solid.

Analysis: HPLC-MS: R_(t)=0.45 min (method J), M+H=510

Step 2: Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 9)

A solution of 90 mg (80% per NMR) of tert-butyl4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylatein 2 mL TFA was stirred at room temperature for 15 min. The reactionmixture was purified by rpHPLC (SunfireC18, acetonitrile/water, TFA) toyield after lyophilisation 83 mg of Example 9 as solid.

Analysis: HPLC-MS: R_(t)=0.32 min (method J), M+H=410

Synthesis of(4R)-4-[(1R)-1-[6-[1-(4,4-Difluorocyclohexyl)pyrazol-4-yl]-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 10)

A mixture of 100 mg[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronicacid 11.1, 87 mg 4-bromo-1-(4,4-difluoro-cyclohexyl)pyrazole 3.12, 27 mg1,1′-bis(diphenylphospino)ferrocenedichloropalladium(II) (complex withDCM (1:1)) and 493 μL 2M aqueous sodium carbonat solution in 2 mLdioxane was stirred at 120° C. for 15 min under microwave irradiation.The reaction mixture was filtered and purified by rpHPLC to yield afterlyophilisation 23 mg of Example 10 as solid.

Analysis: HPLC-MS: R_(t)=0.535 min (method C), M+H=445

¹H NMR (DMSO, 400 MHz) δ=1.38 (3H, d), 1.58 (9H, s), 2.00-2.20 (10H, m),2.73-2.86 (1H, m), 3.11-3.16 (m, 1H), 3.38 (1H, t), 4.09 (3H, s),4.39-4.49 (1H, m), 5.50-5.61 (1H, m), 7.31 (1H, s), 7.50 (1H, s), 8.00(1H, s), 8.26 (1H, s), 8.40 (s, 1H).

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]indazol-4-yl]oxyethyl]pyrrolidin-2-one(Example 15)

To a mixture of 100 mg(4R)-4-[(1R)-1-[2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one11.3, 95 mg 4-bromo-1-(3,3,3-trifluoro-propyl)pyrazole 3.15 and 9.1 mg1,1′-bis(triphenylphosphine)palladium(II) chloride in 1.5 mL ethanol(80% with toluene) was added 389 μL 2M aqueous sodium carbonat solution.The resulting mixture was stirred at 100° C. for 1 h under microwaveirradiation. The reaction mixture was diluted with water and extractedwith DCM. The combined organic phases were concentrated in vacuo. Thecrude residue was purified by flash chromatography (heptane/ethylacetate/methanol) and by rpHPLC to yield 27 mg (yield: 25%) of Example15 as solid.

Analysis: HPLC-MS: R_(t)=2.33 min (method R), M+H=422

The following Examples were synthesized in analogous manner to Example15.

Bromide (corresponding to Example formula 3) Yield Analysis Example 163-bromo-1H- 12 mg HPLC-MS: 3-[2-methyl-4-[(1R)-1-[(3R)-5-indazole-5-carbonitrile (12%) R_(t) = 2.20 min oxopyrrolidin-3-yl]- 3.16(method R), ethoxy]indazol-6-yl]-1H- M + H = 401 indazole-5-carbonitrileExample 41 2-bromo-5-fluoro- 19 mg HPLC-MS:(4R)-4-[(1R)-1-[6-(5-fluoro-2- pyridine 3.17 (27%) R_(t) = 2.23 minpyridyl)-2-methyl-indazol-4- (Method R), yl]oxyethyl]pyrrolidin-2-oneM + H = 355 Example 42 4-(4-bromo- 34 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-[4- phenyl)-1-methyl- (40%) R_(t) = 1.53 min(1-methyl-4-piperidyl)- piperidine 3.18 (method R),phenyl]indazol-4-yl]oxyethyl]- M + H = 433 pyrrolidin-2-one Example 433-bromoimidazo- 21 mg HPLC-MS: 3-[2-methyl-4-[(1R)-1-[(3R)-5-[1,2-a]pyridine-6- (26%) R_(t) = 1.65 minoxopyrrolidin-3-yl]ethoxy]indazol- carbonitrile 3.14 (method R),6-yl]imidazo[1,2- M + H = 401 a]pyridine-6-carbonitrile

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-(4-morpholinophenyl)indazol-4-yl]oxyethyl]-pyrrolidin-2-one(Example 22)

To a mixture of 105 mg(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one7.4, 96 mg (4-morpholinophenyl)boronic acid 4.46 and 10.9 mg1,1′-bis(triphenylphosphine)palladium(II) chloride in 1.58 mL ethanol(80% with toluene) was added 466 μL 2M aqueous sodium carbonat solution.The resulting mixture was stirred at 95° C. for 1 h. The reactionmixture was diluted with water and extracted with DCM. The combinedorganic phases were concentrated in vacuo. The crude residue waspurified by flash chromatography (heptane/ethyl acetate/methanol) and byrpHPLC to yield 74 mg (yield: 56%) of Example 22 as solid.

Analysis: HPLC-MS: R_(t)=2.35 min (method R), M+H=421

The following Examples were synthesized in analogous manner to Example22, but with modified reaction time.

Boronic acid/ester Yield (corresponding to Reaction Example formula 4)time Analysis Example 14 1-methyl-3-(4,4,5,5- 49 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6- tetramethyl-1,3,2- (66%) R_(t) = 1.86 min(1-methylpyrazol-3- dioxaborolan-2- 2 h (method R),yl)indazol-4-yl]oxyethyl]- yl)pyrazole 4.49 M + H = 340 pyrrolidin-2-oneExample 18 1-tert-butyl-4- 95 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1-tert-(4,4,5,5-tetramethyl- (80%) R_(t) = 2.35 minbutylpyrazol-4-yl)-2-methyl- 1,3,2-dioxaborolan- 1 h (method R),indazol-4- 2-yl)pyrazole 4.19 M + H = 382 yl]oxyethyl]pyrrolidin-2-one¹H NMR (DMSO, 500 MHz) δ = 1.28 (3H, d, J = 6.1 Hz), 1.56 (9H, s),2.19-2.35 (2H, m), 2.74 (1H, h, J = 8.2 Hz), 3.12 (1H, dd, J = 9.6, 6.8Hz), 3.37 (1H, t, J = 9.0 Hz), 4.08 (3H, s), 4.76 (1H, d, J = 6.0 Hz),6.71 (1H, s), 7.34 (1H, s), 7.57 (1H, s), 7.91 (1H, s), 8.22 (1H, s),8.29 (1H, s) Example 26 1-methyl-4-[4- 97 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6- (4,4,5,5-tetramethyl- (72%) R_(t) = 1.43 min[4-(4-methylpiperazin-1- 1,3,2-dioxaborolan- 1.5 h   (method R),yl)phenyl]indazol-4- 2-yl)phenyl]- M + H = 434yl]oxyethyl]pyrrolidin-2-one piperazine 4.35 Example 27 2-isopropoxy-5-78 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(6- (4,4,5,5-tetramethyl- (90%) R_(t) =2.75 min isopropoxy-3-pyridyl)-2- 1,3,2-dioxaborolan- 1.5 h   (methodR), methyl-indazol-4- 2-yl)pyridine 4.48 M + H = 395yl]oxyethyl]pyrrolidin-2-one Example 28 (1-methylindazol-5- 67 mgHPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6- yl)boronic acid 4.47 (78%) R_(t) =2.30 min (1-methylindazol-5-yl)indazol- 1.5 h   (method R),4-yl]oxyethyl]pyrrolidin-2- M + H = 390 one Example 32 1-methyl-4-[4- 75mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6- (4,4,5,5-tetramethyl- (67%)R_(t) = 1.75 min [4-(4-methylpiperazin-1-yl)-3- 1,3,2-dioxaborolan- 1 h(method R), (trifluoromethyl)phenyl]- 2-yl)-2-(trifluoro- M + H = 502indazol-4-yl]oxyethyl]pyrrolidin- methyl)phenyl]piperazine 2-one 4.16Example 33 2-[4-(4,4,5,5- 45 mg HPLC-MS: 2-[4-(4,4,5,5-tetramethyl-tetramethyl-1,3,2- (45%) R_(t) = 2.25 min 1,3,2-dioxaborolan-2-dioxaborolan-2- 1 h (method R), yl)phenyl]-1,2-thiazolidineyl)phenyl]-1,2- M + H = 455 1,1-dioxide thiazolidine 1,1- dioxide 4.14Example 36 1-methyl-5-(4,4,5,5- 66 mg HPLC-MS:(4R)-4-[(1R)-1-[6-(3-amino-1- tetramethyl-1,3,2- (73%) R_(t) = 1.97 minmethyl-indazol-5-yl)-2- dioxaborolan-2- 1 h (method R),methyl-indazol-4- yl)indazol-3-amine M + H = 405yl]oxyethyl]pyrrolidin-2-one 4.15 Example 38 4-[4-(4,4,5,5- 43 mgHPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6- tetramethyl-1,3,2- (40%) R_(t) =3.11 min [4-morpholino-3- dioxaborolan-2-yl)-2- 1 h (method R),(trifluoromethyl)phenyl]indazol- (trifluoromethyl)- M + H = 4894-yl]oxyethyl]pyrrolidin-2- phenyl]morpholine one 4.18 Example 401-(difluoromethyl)-4- 53 mg HPLC-MS: (4R)-4-[(1R)-1-[6-[1-(4,4,5,5-tetramethyl- (63%) R_(t) = 2.16 min(difluoromethyl)pyrazol-4-yl]- 1,3,2-dioxaborolan- 1 h (method R),2-methyl-indazol-4- 2-yl)pyrazole 4.17 M + H = 376yl]oxyethyl]pyrrolidin-2-one Example 47 1-tetrahydropyran-4- 68 mgHPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6- yl-4-(4,4,5,5- (75%) R_(t) = 1.95min (1-tetrahydropyran-4- tetramethyl-1,3,2- 1.5 h   (method R),ylpyrazol-4-yl)indazol-4- dioxaborolan-2- M + H = 410yl]oxyethyl]pyrrolidin-2-one yl)pyrazole 4.32 ¹H NMR (DMSO, 500 MHz) δ =1.29 (3H, d, J = 6.1 Hz), 1.92-2.08 (4H, m), 2.18-2.35 (2H, m), 2.75(1H, dt, J = 14.9, 7.6 Hz), 3.12 (1H, dd, J = 9.5, 6.8 Hz), 3.38 (1H, t,J = 9.1 Hz), 3.48 (2H, td, J = 11.4, 3.1 Hz), 3.98 (2H, d, J = 11.2 Hz),4.08 (3H, s), 4.40 (1H, tt, J = 10.1, 5.1 Hz), 4.74 (1H, p, J = 6.0 Hz),6.69 (1H, s), 7.33 (1H, s), 7.58 (1H, s), 7.94 (1H, s), 8.23 (1H, s),8.31 (1H, s) Example 48 7-chloro-2-(4,4,5,5- 65 mg HPLC-MS:(4R)-4-[(1R)-1-[6-(7-chloro- tetramethyl-1,3,2- (71%) R_(t) = 3.05 min1H-indol-2-yl)-2-methyl- dioxaborolan-2-yl)- 1 h (method R),indazol-4-yl]oxyethyl]- 1H-indole 4.39 under M + H = 409/411pyrrolidin-2-one microwave irradiation Example 49 1-methyl-4-[4- 64 mgHPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6- (4,4,5,5-tetramethyl- (68%) R_(t) =1.25 min [1-(1-methyl-4-piperidyl)- 1,3,2-dioxaborolan- 1 h (method R),pyrazol-4-yl]indazol-4-yl]- 2-yl)pyrazol-1- M + H = 423oxyethyl]pyrrolidin-2-one yl]piperidine 4.21

Synthesis of(4R)-4-[(1R)-1-(2-methyl-6-thiazol-4-yl-indazol-4-yl)oxyethyl]pyrrolidin-2-one(Example 29)

A mixture of 75 mg(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one(9.2), 102 μL tributyl(thiazol-4-yl)stannane and 7.8 mg1,1′-bis(triphenylphosphine) palladium(II) chloride in 1.5 mL dioxanewas stirred at 95° C. for 18 h. The reaction mixture was concentrated invacuo. The crude residue was purified by flash chromatography(heptane/ethyl acetate/methanol) and by rpHPLC to yield 13 mg (yield:19%) of Example 29 as solid.

Analysis: HPLC-MS: R_(t)=1.98 min (method R), M+H=343

The following Example was synthesized in analogous manner to Example 29,but with modified reaction time.

Stannane Yield (corresponding to Reaction Example formula 4) timeAnalysis Example 35 2-difluoromethyl- 49 mg HPLC-MS:(4R)-4-[(1R)-1-[6-[2- 4- (42%) R_(t) = 2.50 min (difluoromethyl)thiazol-tributylstannanyl- 1 h (method R), 4-yl]-2-methyl-indazol- thiazole 4.1M + H = 393 4-yl]- oxyethyl]pyrrolidin- 2-one

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-[1-(4-piperidyl)pyrazol-4-yl]indazol-4-yl]oxyethyl]pyrrolidin-2-one(Example 45)

To a mixture of 125 mg(4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one7.5, 167 mg tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate4.41 and 13 mg 1,1′-bis(triphenylphosphine)palladium (II) chloride in1.88 mL ethanol (80% with toluene) was added 554 μL 2M aqueous sodiumcarbonat solution. The resulting mixture was stirred at 95° C. for 1 h.The reaction mixture was diluted with water and extracted with DCM. Thecombined organic phases were concentrated in vacuo. The crude residuewas purified by flash chromatography (heptane/ethyl acetate/methanol).The residue was dissolved in 2 mL DCM, 500 μL TFA were added and theresulting mixture was stirred at room temperature for 1 h. The reactionmixture was purified by flash chromatography (DCM/methanol/ammonia) andby elution through a SCX (Biotage SCX-3) column and subsequent rpHPLC toyield 92 mg (yield: 61%) of Example 45 as solid.

Analysis: HPLC-MS: R_(t)=1.25 min (method R), M+H=409

Synthesis of(4R)-4-[(1R)-1-[6-(6-Cyclopropyl-3-pyridyl)-2-methyl-pyrazolo[4,3-c]pyridine-4-yl]oxyethyl]pyrrolidin-2-one(Example 50)

To a mixture of 50 mg(4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one7.1, 94 mg2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine4.23 and 20 mg 1,1′-bis(triphenylphosphine)palladium(II) chloride in 1mL DMA was added 400 μL 2M aqueous sodium carbonat solution. Thereaction mixture was stirred at 130° C. for 25 min under microwaveirradiation. The reaction mixture was filtered through rpSiO₂, washedwith methanol and purified by rpHPLC to yield after lyophilisation 22 mg(yield: 37%) of Example 50 as solid.

Analysis: HPLC-MS: R_(t)=0.69 min (method U), M+H=378

The following Examples were synthesized in analogous manner to Example50.

Boronic acid/ester (corresponding to Example formula 4) Yield AnalysisExample 2 1-tert-butyl-4- 1.11 g HPLC-MS: (4R)-4-[(1R)-1-[6-(1-tert-(4,4,5,5- (54%) R_(t) = 0.50 min butylpyrazol-4-yl)-2-methyl-tetramethyl-1,3,2- (method C), pyrazolo[4,3-c]pyridin-4- dioxaborolan-2-M + H = 383 yl]oxyethyl]pyrrolidin-2-one yl)pyrazole 4.19 ¹H NMR (DMSO,400 MHz) δ = 1.38 (3H, d), 1.58 (9H, s), 2.20-2.34 (2H, m), 2.73-2.85(1H, m), 3.11-3.19 (m, 1H), 3.38 (1H, t), 4.10 (3H, s), 5.50-5.60 (1H,m), 7.33 (1H, s), 7.52 (1H, s), 7.98 (1H, s), 8.26 (1H, s), 8.41 (s,1H). Example 51 2-difluoromethyl-5-   24 mg HPLC-MS:(4R)-4-[(1R)-1-[6-[6- (4,4,5,5- (40%) R_(t) = 0.65 min(difluoromethyl)-3-pyridyl]-2- tetramethyl-1,3,2- (method U), M + H =388 methyl-pyrazolo[4,3-c]pyridin- dioxaborolan-2-yl)-4-yl]oxyethyl]pyrrolidin-2-one pyridine 4.5 Example 52(3,4,5-trimethoxy-   35 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-phenyl)boronic acid (54%) R_(t) = 0.67 min (3,4,5-trimethoxyphenyl)-4.25 (method W), M + H = 427 pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one Example 57 1-(2-methoxy-   36 mg HPLC-MS:(4R)-4-[(1R)-1-[6-[1-(2- ethyl)-4-(4,4,5,5- (62%) R_(t) = 0.53 minmethoxyethyl)pyrazol-4-yl]-2- tetramethyl-1,3,2- (method W), M + H = 385methyl-pyrazolo[4,3-c]pyridin- dioxaborolan-2-4-yl]oxyethyl]pyrrolidin-2-one yl)pyrazole 4.27 Example 581-ethyl-4-(4,4,5,5-   31 mg HPLC-MS: (4R)-4-[(1R)-1-[6-(1-tetramethyl-1,3,2- (45%) R_(t) = 0.48 min ethylpyrazol-4-yl)-2-methyl-dioxaborolan-2- (method V), M + H = 355 pyrazolo[4,3-c]pyridin-4-yl)pyrazole 4.28 yl]oxyethyl]pyrrolidin-2-one Example 61 [6-(trifluoro-  15 mg HPLC-MS: (4R)-4-[(1R)-1-[2-methyl-6-[6-methyl)-3-pyridyl]boronic (23%) R_(t) = 0.65 min (trifluoromethyl)-3-acid 4.29 (method V), M + H = 406 pyridyl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one Example 63 1-methyl-4-   26 mg HPLC-MS:(4R)-4-[(1R)-1-[2-methyl-6-(1- (4,4,5,5- (50%) R_(t) = 0.44 minmethylpyrazol-4- tetramethyl-1,3,2- (method V), M + H = 341yl)pyrazolo[4,3-c]pyridin-4- dioxaborolan-2-yl]oxyethyl]pyrrolidin-2-one yl)pyrazole 4.31

Synthesis of(4R)-4-[(1R)-1-[6-(3-Methoxy-4-tetrahydropyran-4-yloxy-phenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 73)

A mixture of 68 mg of Example 8, 59 mg of tetrahydropyran-4-yl4-methylbenzenesulfonate and 39 mg potassium carbonate in 2 mL DMF wasstirred at 80° C. for 3 h and at 100° C. for 10 h. The reaction mixturewas diluted with water and extracted with DCM. The combined organicphases were concentrated in vacuo. The resulting residue was purified byrpHPLC to yield after lyophilisation 37 mg of Example 73 as solid.

Analysis: HPLC-MS: R_(t)=0.70 min (method W), M+H=467

Synthesis of(4R)-4-[(1R)-1-[2-Methyl-6-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 82)

To a mixture of 68 mg of Example 9 and 31 mg sodium acetate in 3 mL DCMand 0.5 mL methanol was added 17 μL formaldehyde (aqueous 37%). Theresulting mixture was stirred at room temperature for 10 min, before 46mg sodium triacetoxyborohydride was added. The reaction mixture wasstirred for 1.75 h before quenched with water. The organic solvent wasremoved by destillation. The resulting residue was purified by rpHPLC toyield after lyophilisation 64 mg of Example 82 as solid.

Analysis: HPLC-MS: R_(t)=0.28 min (method X), M+H=424

Synthesis of(4R)-4-[(1R)-1-[6-[1-(Difluoromethyl)imidazol-4-yl]-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one(Example 83) and2-Methyl-6-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]-5H-pyrazolo[4,3-c]pyridin-4-one(Example 13)

To a mixture of 300 mg (crude)[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronicacid 11.1, 60 mg 4-bromo-1-(difluoromethyl)imidazole and 41 mg1,1′-bis(diphenylphospino)ferrocenedichloro palladium(II) (complex withDCM (1:1)) in 2 mL dioxane and 0.5 mL methanol was added 670 μL 2Maqueous sodium carbonat solution. The reaction mixture was stirred at140° C. for 15 min under microwave irradiation. The reaction mixture wasfiltered through Agilent PL-Thiol MP-SPE, washed with methanol andpurified by rpHPLC to yield after lyophilisation 9 mg of Example 83 and4 mg of Example 13 as solids.

Analysis (Example 83): HPLC-MS: R_(t)=0.43 min (method C), M+H=377

Analysis (Example 13): HPLC-MS: R_(t)=0.38 min (method C), M+H=408

4.5 Analytical Methods

The Example compounds prepared according to the foregoing synthesisschemes were characterised by the following chromatographic methodsand/or NMR spectroscopy.

4.5.1 Chromatographic Methods (HPLC-MS Methods)

Method A

Column: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μm Column supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃][Acetonitril] [ml/min] [° C.] 0.00 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60Method B:

Column: Sunfire C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 1.8 60 0.25 95 5 1.8 60 1.70 0 1001.8 60 1.75 0 100 2.5 60 1.90 0 100 2.5 60Method C:

Column: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μm Column supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃][Acetonitril] [ml/min] [° C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60Method D:

Column: XBridge C18, 2.1 × 20 mm, 2.5 μm Column Supplier: WatersGradient/ Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.10% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 1001.4 60 1.1 0 100 1.4 60Method E:

Column: Sunfire C18, 2.1 × 20 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.10% TFA][Methanol] [ml/min] [° C.] 0.00 99 1 1.3 60 0.15 99 1 1.3 60 1.10 0 1001.3 60 1.25 0 100 1.3 60Method F:

Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60Method G:Eluent A: Water/0.2% KH₂PO₄ pH=3Eluent B: Acetonitrile

Time [min] % A % B Flow rate [mL/min] 0.00 80 20 1.50 5.00 20 80 1.508.00 20 80 1.50

The stationary phase used was a Inertsil C8-3 (GL Sciences), 5 μm;dimension: 100×4.0 mm,

(column temperature: constant at 30° C.). Detection UV 220 nm.

Method H:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % A % B Flow rate [mL/min] 00.00 90 10 1.0 20.00 90 10 1.0

The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm;dimension: 150×4.6 mm, (column temperature: constant at 10° C.).Detection DAD 225 nm.

Method I:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % A % B Flow rate [mL/min] 00.00 90 10 1.0 25.00 90 10 1.0

The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm;dimension: 150×4.6 mm, (column temperature: constant at 10° C.).

Detection DAD 225 nm.

Method J:

Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0100 1.5 60 1.10 0 100 1.5 60Method K:Column: Waters Atlantis dC18 (2.1×50 mm, 3 μm column)Flow rate: 1 mL/minSolvent A: 0.1% Formic acid/waterSolvent B: 0.1% Formic acid/acetonitrileInjection volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 2.5 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 2.5 to 2.7 minutes, 100% solvent B; 2.71 to3.0 minutes, 95% solvent A+5% solvent B.MS detection using Waters LCT Premier, QTof micro, ZQ or ShimadzuLCMS2010EVUV detection using Waters 2996 photodiode array, Waters 2998 photodiodearray, Waters 2487 UV or Shimadzu SPD-M20A PDAMethod L:

Column: XBridge C18, 4.6 × 30 mm, 3.5 μm Column Supplier: WatersGradient/Solvent % Sol [H₂O, 0.1% % Sol Flow Temp Time [min] NH3] [ACN][ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 560Method M:Column: Waters SymmetryShield RP8 (2.1×50 mm, 3.5 μm column)Flow rate: 1 mL/minSolvent A: 0.1% Formic acid/waterSolvent B: 0.1% Formic acid/acetonitrileInjection volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 2.2 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 2.2 to 2.7 minutes, 100% solvent B; 2.71 to3.0 minutes, 95% solvent A+5% solvent B.MS detection using Waters LCT Premier, QTof micro, ZQ or ShimadzuLCMS2010EVUV detection using Waters 2996 photodiode array, Waters 2998 photodiodearray, Waters 2487 UV or Shimadzu SPD-M20A PDAMethod N:

Column: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0100 1.6 60 1.10 0 100 1.6 60Method O:

Column: Xbridge BEH Phenyl, 2.1 × 30 mm, 1.7 μm Column supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% NH3][Acetonitril] [ml/min] [° C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60Method P:Column: Supelco Ascentis Express (2.1×30 mm, 2.7 μm column)Flow rate: 1 ml/minSolvent A: 0.1% Formic acid/waterSolvent B: 0.1% Formic acid/acetonitrileInjection volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 1.5 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 1.5 to 1.6 minutes, 100% solvent B; 1.60 to1.61 minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 1.61 to 2.00 minutes, 95% solvent A+5% solvent B.MS detection using Waters LCT Premier, QTof micro, ZQ or ShimadzuLCMS2010EVUV detection using Waters 2996 photodiode array, Waters 2998 photodiodearray, Waters 2487 UV or Shimadzu SPD-M20A PDAMethod QColumn: Atlantis d C18; 50×3 mm; 3μFlow rate: 0.6 ml/minSolvent A: 0.1% Formic acid in waterSolvent B: 0.1% Formic acid in acetonitrileInjection Volume: 5 μLColumn temperature: 35° C.UV Detection wavelength: Spectra A max (with scan in the region of200-400 nm)Eluent: 0 to 3.5 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 3.5 to 3.8 minutes, 100% solvent B; 3.8 to3.9 minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 3.9 to 4.5 minutes, 95% solvent A+5% solvent B.MS detection using Waters 3100, SQ detector, ES +ve and −ve modes (Conevoltage: 30V, Capillary voltage 3.0 KV)UV detection using Waters 2996 photodiode arrayMethod R:Column: Phenomenex Kinetex-XB C18 (2.1×100 mm, 1.7 μm column)Flow rate: 0.6 mL/minSolvent A: 0.1% Formic acid/waterSolvent B: 0.1% Formic acid/acetonitrileInjection volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 5.3 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 5.3 to 5.8 minutes, 100% solvent B; 5.80 to5.82 minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 5.82 to 7 mins, 95% solvent A+5% solvent BMS detection using Waters SQDUV detection using Waters Acquity photodiode arrayMethod S:

Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60Method T:Column: Phenomenex Gemini C18 (2.0 mm×100 mm, 3 μm column)Flow rate: 0.5 mL/minSolvent A: 2 mM Ammonium bicarbonate modified to pH 10 with AmmoniumHydroxide/waterSolvent B: AcetonitrileInjection volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 5.5 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 5.5 to 5.9 minutes, 100% solvent B; 5.90 to5.92 minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 5.92 to 9.00 minutes, 95% solvent A+5% solvent B.Method U:

Column: XBridge C18_3.0 × 30 mm, 2.5 μm Column producer: WatersDescription: Gradient/Solvent % Sol [H₂O % Sol Flow Temp Time [min] 0.1%NH₄OH] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0Method V:

Column: XBridge C18_3.0 × 30 mm, 2.5 μm Column producer: WatersGradient/Solvent % Sol [H₂O 0.1% % Sol Flow Temp Time [min] NH₄OH][Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.060.0 1.4 0.0 100.0 2.0 60.0Method W:

Column: Sunfire C18_3.0 × 30 mm, 2.5 μm Column producer: WatersDescription: Gradient/Solvent % Sol [H2O 0.1% % Sol Flow Temp Time [min]TFA] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.02.0 60.0 1.4 0.0 100.0 2.0 60.0Method X:

Column: Sunfire C18_2.1 × 50 mm, 2.5 μm Column producer: WatersDescription: Gradient/Solvent % Sol [H₂O % Sol [Acetonitrile Flow TempTime [min] 0.1% TFA] 0.08% TFA] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.00.75 0.0 100.0 1.5 60.0 0.85 0.0 100.0 1.5 60.0Method Y:

Device description: Waters Acquity with 3100 MS Column: XBridge BEHC18_3.0 × 30 mm, 1.7 μm Column producer: Waters Description:Gradient/Solvent % Sol [H₂O 0.1% % Sol Flow Temp Time [min] NH₄OH][Acetonitrile] [ml/min] [° C.] 0.0 95.0 5.0 1.5 60.0 0.7 0.1 99.9 1.560.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0Method Z:Column: Waters Atlantis dC18 (2.1×100 mm, 3 μm column)Flow rate: 0.6 mL/minSolvent A: 0.1% Formic acid/waterSolvent B: 0.1% Formic acid/acetonitrileInjection Volume: 3 μLColumn temperature: 40° C.UV Detection wavelength: 215 nmEluent: 0 to 5 minutes, constant gradient from 95% solvent A+5% solventB to 100% solvent B; 5 to 5.4 minutes, 100% solvent B; 5.4 to 5.42minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 5.42 to 7.00 minutes, 95% solvent A+5% solvent B.MS detection using Waters LCT Premier, QT of micro, ZQ or ShimadzuLCMS2010EVUV detection using Waters 2996 photodiode array, Waters 2998 photodiodearray, Waters 2487 UV or Shimadzu SPD-M20A PDAMethod Z1:

Method Name: Column: Sunfire, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 604.5.2 NMR SpectroscopyConfiguration of the Bruker DRX 500 MHz NMR

High performance digital NMR spectrometer, 2-channel microbay consoleand Windows XP host workstation running Topspin version 1.3.

Equipped with:

-   -   Oxford instruments magnet 11.74 Tesla (500 MHz proton resonance        frequency)    -   B-VT 3000 temperature controller    -   GRASP II gradient spectroscopy accessory for fast acquisition of        2D pulse sequences    -   Deuterium lock switch for gradient shimming    -   5 mm Broad Band Inverse geometry double resonance probe with        automated tuning and matching (BBI ATMA). Allows ¹H observation        with pulsing/decoupling of nuclei in the frequency range ¹⁵N and        ³¹P with ²H lock and shielded z-gradient coils.        Configuration of the Bruker DPX 400 MHz NMR

High performance one bay Bruker 400 MHz digital two channel NMRspectrometer console and Windows XP host workstation running XwinNMRversion 3.5.

Equipped with:

-   -   Oxford instruments magnet 9.39 Tesla (400 MHz proton resonance        frequency)    -   B-VT 3300 variable temperature controller unit    -   Four nucleus (QNP) switchable probe for observation of ¹H, ¹³C,        ¹⁹F and ³¹P with ²H lock        Configuration of the Bruker 500 MHz NMR

High performance digital NMR spectrometer, 2-channel one bay console andLinux host workstation running Topspin version 2.1 PL6.

Equipped with:

-   -   Bruker-Biospin AVANCE III 500A magnet 11.75 Tesla (500 MHz        proton resonance frequency)    -   B-VT 3000 temperature controller    -   5 mm Multinuclear Broad Band fluorine observe (BBFO) probe with        digital tuning covering the range from ¹⁵N and ³¹P as well as        ¹⁹F with ¹H decoupling.        Configuration of the Bruker DPX 400 MHz NMR

High performance digital NMR spectrometer, 2-channel microbay consoleand Linux host workstation running Topspin version 2.1 PL6

Equipped with:

-   -   Bruker-Biospin AVANCE III DPX400C magnet 9.40 Tesla (400 MHz        proton resonance frequency)    -   B-VT 3200 variable temperature controller unit        5 mm Multinuclear Broad Band fluorine observe (BBFO) probe with        digital tuning covering the range from ¹⁵N and ³¹P as well as        ¹⁹F with ¹H decoupling.

5. EXAMPLES

The following Examples were prepared analogously to the methods ofsynthesis described above. These compounds are suitable as SYKinhibitors and have IC₅₀-values with regard to SYK-inhibition of lessthan or equal to 1 μmol. Additionally these compounds exhibit a verygood SYK-selectivity which means that—whereas SYK is inhibitedeffectively—other kinases such as Aurora B (AURB), FLT-3 and GSK 3β arenot or almost not inhibited at all. Consequently undesired side effectsof these effective SYK-inhibitors of the invention are minimized.

AURB phosphorylates Ser10 and Ser28 on histone H3, a key event inmitosis and cellular proliferation. Inhibition of AURB therefore has thepotential to block cellular proliferation, and could compromise tissuesthat exhibit a high cellular turnover, such as the intestine or the bonemarrow. It is therefore desired to avoid parallel AURB inhibition of aneffective SYK inhibitor to improve the overall clinical safety profileof the compound. Consequently all example compounds show IC₅₀-valueswith regard to Aurora B inhibition of more than 1 μM, preferably morethan 6 μM, more preferably more than 10 μM, more preferably more than 30μM, more preferably of more than 45 μM, particularly preferably morethan 50 μM. The AURB-IC₅₀/SYK-IC₅₀-ratios of all example compounds arepreferably more than 30, more preferably more than 100.

FLT-3 is a tyrosine kinase receptor. When an FLT-3 ligand binds to thereceptor, the intrinsic tyrosine kinase activity of the receptor isactivated, which in turn phosphorylates and activates signaltransduction molecules (such as SHC) which in turn propagates the signalin the cell. Signaling through FLT-3 plays a role in cell survival,proliferation, and differentiation and is important for lymphocyte (Bcell and T cell) development. It is therefore desired to avoid parallelFLT-3 inhibition of an effective SYK inhibitor to improve the overallclinical safety profile of the compound. Consequently all examplecompounds of the instant invention show IC₅₀-values with regard to FLT-3inhibition of more than 0.30 μM, preferably more than 1 μM, morepreferably more than 10 μM, particularly preferably more than 30 μM. TheFLT-3-IC₅₀/SYK-IC₅₀-ratios of all example compounds are preferably morethan 10, more preferably more than 30.

Glycogen synthase kinase 3 beta (GSK 3β) is a proline-directedserine-threonine kinase that is prominent in the TGF-β and Wntintracellular signalling pathways. GSK 3β facilitates a number ofintracellular signalling pathways including the activation of β-catenincomplex. In adults, GSK 3β is involved in cellular proliferation andenergy metabolism, whilst in neonates is involved in neuronal celldevelopment and body pattern formation. It is therefore desired to avoidparallel GSK3β inhibition of an effective SYK inhibitor to improve theoverall clinical safety profile of the compound. Consequently allexample compounds of the invention show IC₅₀-values with regard to GSK3β inhibition of more than 1 μM, preferably of more than 10 μM.

Further it is desirable for an SYK-inhibitor to have certain human livermicrosomal stability (corresponding to CI<60% Q_(h); % Q_(h)=percentageof liver blood flow). Otherwise it will be difficult to reach anadequate plasma level of the SYK-inhibitor in the patient to be treated.

The IC₅₀-values with respect to SYK-inhibition, with respect to Aurora Binhibition, with respect to FLT3-inhibition and with respect toGSKbeta-inhibition as well as the human liver microsomal stablities (CI[% Q_(h)]) for each of the individual example substances are shown inthe following Table 1 and were experimentally determined as follows:

5.1 Syk Kinase Test

Recombinant human Syk (amino acids 342-635) was expressed as a fusionprotein with an N-terminal GST tag, affinity-purified and deep-frozen ata concentration of approx. 50-100 μM in storage buffer (25 mM HEPESpH7.5; 25 mM MgCl₂; 5 mM MnCl₂; 50 mM KCl; 0.2% BSA; 0.01% CHAPS; 100 μMNa₃VO₄; 0.5 mM DTT, 10% glycerol) at −80° C. until use.

The catalytic activity of the GST-Syk kinase fusion protein wasdetermined using the Kinase Glo® Luminescence Kinase test (Promega;V6712). In this homogeneous test the amount of ATP remaining after thekinase reaction is quantified by a luciferin-luciferase reaction usingluminescence. The luminescence signal obtained correlates with theamount of ATP still present and thus correlates inversely with theactivity of the kinase.

Method

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and diluted in DMSO to a concentration of 1 mM. Serial Dilution isdone in 100% DMSO. All further dilutions of the substances were carriedout with test buffer (25 mM HEPES pH7.5; 25 mM MgCl₂; 5 mM MnCl₂; 50 mMKCl; 0.2% HSA; 0.01% CHAPS; 100 μM Na₃VO₄; 0.5 mM DTT). Dilution stepsand concentration range were adapted according to need. 7 μl aliquots ofthese dilutions were transferred into a 384-well Optiplate (PerkinElmer, #6007290). GST-Syk was diluted to 12 nM in the test buffer and 5μl of this dilution were used in the kinase test (final concentration ofSyk=4 nM in a total volume of 15 μl). After 15 minutes incubation atroom temperature 3 μl of a mixture of 750 nM ATP and 100 μg/ml poly(L-Glutamic acid L-Tyrosine 4:1), Fluka #81357) in test buffer wereadded to each well and the incubation was continued for a further 60minutes at room temperature.

Positive controls are the reaction mixtures that contain no testsubstance; negative controls (blanks) are reaction mixtures that containno kinase.

After 60 minutes, 10 μl Kinase-Glo® solution (Promega, Cat. # V6712)(heated to room temperature) were added to each well and incubation wascontinued for a further 15 minutes. The plates were read in EnvisionLuminescence Reader (Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured relative light units (RLU). For data evaluation andcalculation, the measurement of the negative control was set as 100%ctrl and the measurement of the positive control was set as 0% ctrl.Based on this values the % value for the measurement of each substanceconcentration was calculated using an Assay Explorer software(Accelrys). Normally, the % ctrl values calculated are between 0% and100% values but may also occur outside these limits in individual casesbased on variability or compound characteristics. The IC₅₀ values werecalculated from the % ctrl values using Assay Explorer software.Calculation:[y=(a−d)/(1+(x/c)^b)+d] a=low value, d=high value; x=conc M;c=IC50 M; b=hill; y=% ctrl.

5.2 Aurora B Kinase Test

Recombinant human Aurora B (amino acids 1-344, clone number DU1773,Molecular weight 40.2 kDa, University of Dundee) was expressed as afusion protein with an N-terminal His tag, affinity-purified anddeep-frozen at a concentration of approx. 0.25-0.5 mg/ml in storagebuffer (50 mM Tris-HCl pH 8; 25 mM Na-β-glycerophosphat; 0.1 mM EGTA;150 mM NaCl; 0.03% Brij-35; 1 mM DTT and 10% glycerol) at −80° C. untiluse.

The activity of the Aurora B kinase protein was determined using the ADPGlo® Luminescence Kinase test (Promega; V9103X). In this homogeneoustest the amount of ADP remaining after the kinase reaction is quantifiedby a luciferin-luciferase reaction using luminescence. The luminescencesignal obtained correlates with the amount of ADP still present and thuscorrelates with the activity of the protein kinase.

Method

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and diluted in DMSO to a concentration of 5 mM. Serial Dilution isdone in 1:10 steps in 100% DMSO. All further dilutions of the substanceswere carried out with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1mM EGTA, 60 μM Ultra Pure ATP, 0.01% Brij35, 0.1% BSA, 5 mMβ-Glycerophosphate) until a concentration was reached which was 2.5times above the final test concentration (final concentration of thecompounds: 50 μM to 0.005 nM). 4 μl aliquots of these dilutions weretransferred into a 384-well Optiplate (Perkin Elmer, #6007290).His-Aurora B was diluted to 125 nM in the test buffer and 4 μl of thisdilution were used in the kinase test (final concentration of AuroraB=50 nM in a total volume of 10 μl). After 15 minutes incubation at roomtemperature 2 μl of 250 μM substrate ([LRRLSLGLRRLSLGLRRLSLGLRRLSLG];University of Dundee) in test buffer were added to each well and theincubation was continued for a further 60 minutes at room temperature.

Positive controls are the reaction mixtures that contain no testsubstance; negative controls (blanks) are reaction mixtures that containno kinase.

After 60 minutes, 10 μl ADP-Glo® solution (ADP-Glo Reagent #V912BPromega) (heated to room temperature) were added to each well andincubation was continued for a further 40. minutes. Then 20 μl Kinasedetection mix (Detection Buffer #V913B Promega; Kinase DetectionSubstrate #V914B Promega) were added and incubated for 40 minutes atroom temperature. The plates were read in Envision Luminescence Reader(Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured RLU. For data evaluation and calculation, themeasurement of the negative control was set as 0% ctrl and themeasurement of the positive control was set as 100% ctrl. Based on thisvalues the % value for the measurement of each substance concentrationwas calculated using an Assay Explorer software (Accelrys). Normally,the % ctrl values calculated are between 0% and 100% values but may alsooccur outside these limits in individual cases based on variability orcompound characteristics. The IC₅₀ values were calculated from the %ctrl values using Assay Explorer software. Calculation:[y=(a−d)/(1+(x/c)^b)+d], a=low value, d=high value; x=conc M; c=IC50 M;b=hill; y=% ctrl.

5.3 FLT3 Kinase Test

FLT3 is obtained from Invitrogen in 50 mM Tris (pH7.5); 100 mM NaCl;0.05 mM EDTA, 0.05% NP-40, 2 mM DTT; 50% Glycerol # PV3182; Lot 286671;sequence see below). The enzyme is diluted to 720 nM (35 μg/ml) inenzyme dilution buffer and 10 μl aliquots are stored at −80° C.

The activity of FLT3 is measured using the Z′-LYTETM assay technologyfrom Invitrogen (#PV3191)

Method

The assay is performed in 384 black plates from Corning (#3676) in afinal volume of 10 μl by adding 5 μl of kinase peptide mix and 2.5 μl ofcompound dilution. The reaction is started by addition of 2.5 μl of the4×ATP solution.

Final concentration in assay: FLT3 2 nM, Tyr2 peptide 4 μM, ATP 470 μM(ATP Km for FLT3)

Positive controls are reaction mixtures containing no test compound;negative controls (blanks) are reaction mixtures containing no kinase.As a further control, the phosphopeptide solution is added to wellswithout kinase (=100% phosphorylation control). The non inhibited kinasereaction will result in a phosphorylation corresponding to 20%-30% ofthe phosphorylation control.

The reaction is performed for 1 h at room temperature before 5 μl of thedevelopment solution is added. After a further incubation for 1 h atroom temperature 5 μl of the stop reagent is added. The plates are readon a Flex Station II 384 (Molecular Devices).

To control for any potential inhibition of the protease present in thedevelopment solution, the phosphopeptide is incubated with thedevelopment solution in the presence of the highest concentration of thetest compound (usually 100 μM or 10 μM).

Data Evaluation and Calculation:

The output text file is evaluated in an “MS-Excel—VB-Makro” and“GraphPadPrism” (Version 5) (GraphPad Software Inc.) is used tocalculate the results. Data for the inhibition of FLT3 are reported inM. data for the inhibition of the protease are reported in % CTL.

5.4 GSK 30 Kinase-Test

Human GSK3beta (expressed and prified from SF21 cells) is obtained fromthe University Dundee/Scotland (Dr. James Hastie—Dept. of Biochemistry)in 50 mM Tris (pH7.5); 150 mM NaCl; 0.1 mM EGTA, 270 mM Succrose, 0.1%β-mercaptoethanol, 1 mM benzamidine, 0.2 mM PMSF; sequence see below).The enzyme is diluted to 3.56 μM (168 μg/ml) in enzyme dilution bufferand 6 μl aliquots are stored at −80° C.

The activity of GSK3 kinase protein is measured using the Z′-LYTETMassay technology from Invitrogen (# PV3324).

Method:

The assay is performed in 384 black plates from Corning (#3676) in afinal volume of 10 μl by adding 5 μl of kinase peptide mix and 2.5 μl ofcompound dilution. The reaction is started by addition of 2.5 μl of the4×ATP solution.

Final concentration in assay: GSK3β5 nM, Ser/Thr9 peptide 2 μM, ATP 7 μM(ATP Km for GSK3β)

Positive controls are reaction mixtures containing no test compound;negative controls (blanks) are reaction mixtures containing no ATP. As afurther control, the phosphopeptide solution is added to wells withoutkinase and without ATP (=100% phosphorylation control).

The non inhibited kinase reaction will result in a phosphorylationcorresponding to 20%-30% of the phosphorylation control.

The reaction is performed 1 h at room temperature. After 1h 5 μl of thedevelopment solution is added. After a further incubation for 1 h atroom temperature 5 μl of the stop reagent is added. Finally the platesare read on a Flex Station II 384 (Molecular Devices).

To control for any potential inhibition of the protease present in thedevelopment solution, the phosphopeptide is incubated with thedevelopment solution in the presence of the highest concentration of thetest compound (usually 100 μM).

Data Evaluation and Calculation:

The output text file is evaluated in an “MS-Excel—VB-Makro” and“GraphPadPrism” (Version 5) (GraphPad Software Inc.) is used tocalculate the results. Data for the inhibition of GSK3beta are reportedin M. data for the inhibition of the protease are reported in % CTL.

5.5 Human Liver Microsomal Stability Test

Further it is desirable for an SYK-inhibitor that is sufficientlySYK-specific as described above to have certain human liver microsomalstability (corresponding to CI<60% Q_(h); % Q_(h)=percentage of liverblood flow). Otherwise it will be difficult to reach an adequate plasmalevel of the SYK-inhibitor in the patient to be treated.

Method:

The metabolic degradation for a specific SYK-inhibitor is performed at37° C. with pooled human liver microsomes (human liver microsomes arecommercially available as “BD UltraPool™” by Corning Life Sciences,Fogostraat 12, 1060 LJ Amsterdam, The Netherlands). The final incubationvolume of 100 μl per time point contains TRIS buffer pH 7.6 at RT (0.1M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the testcompound at a final concentration of 1 μM.

Following a short preincubation period at 37° C., the reaction isinitiated by addition of beta-nicotinamide adenine dinucleotidephosphate in its reduced form (NADPH, 1 mM) and terminated bytransfering an aliquot into solvent after different time points.Additionally, the NADPH-independent degradation is monitored inincubations without NADPH, terminated at the last time point.

The quenched (terminated) incubations are then pelleted bycentrifugation (10000 g, 5 min).

An aliquot of the supernatant is assayed by LC-MS/MS for the remainingamount of parent compound. The half-life (t1/2 INVITRO) is determined bythe slope of the semilogarithmic plot of the concentration-time profile.

Data Evaluation and Calculation:

The intrinsic clearance (CL_INTRINSIC) is calculated by considering theamount of protein in the incubation:CL_INTRINSIC[μl/min/mg protein]=(Ln 2/(t1/2 INVITRO[min]*proteincontent[mg/ml]))*1000

The protein content [mg/ml] was determined with the “Bicinchoninic AcidKit” of Sigma Aldrich (commercially available).

The upscaled intrinsic Clearance (CL_UP_INT) is calculated byconsidering the liver weight [g liver/kg body weight] and the microsomalrecovery [mg protein/g liver]:CL_UP_INT[ml/min/kg]=0.001*CL_INTRINSIC*liver weight*microsomal recovery

-   -   with microsomal recovery=45 mg protein/g liver    -   with liver weight=25.7 g liver/kg body weight

The percent hepatic blood flow (% Q_(h)) is finally calculated byconsidering the human liver blood flow Q [ml/min/kg]:% Q _(h)[%]=((Q*CL_UP_INT)/(Q+CL_UP_INT)/Q)*100

-   -   with liver blood flow (Q)=20.7 ml/min/kg.

TABLE 1 SYK- AURB- FLT3- inhibition inhibition inhibition ExampleIC₅₀-value IC₅₀-value IC₅₀-value No. Structure [μM] [μM] [μM] 1

0.0160 >50  3.99 2

0.0144 >50 14.84 3

0.0466 >50 17.45 4 not defined not defined not defined not defined 5 notdefined not defined not defined not defined 6 not defined not definednot defined not defined 7

0.0147 37.30  5.77 8

0.0274 >50 13.50 9

0.0424 >50  3.67 10

0.0218 36.00  8.03 11

0.9352 >50 37.38 12

0.0123 34.09  8.33 13

0.8310 >50 >50 14

0.0421 >50 40.80 15

0.0187 33.40 10.08 16

0.0065 >50 10.60 17

0.0316 >50  1.61 18

0.0046 >50 13.40 19 not defined not defined not defined not defined 20not defined not defined not defined not defined 21 not defined notdefined not defined not defined 22

0.0128 46.90  1.17 23 not defined not defined not defined not defined 24not defined not defined not defined not defined 25 not defined notdefined not defined not defined 26

0.0258 >50  0.95 27

0.1382 >50 26.64 28

0.0335 >50  3.69 29

0.0492 >50 20.56 30 not defined not defined not defined not defined 31not defined not defined not defined not defined 32

0.0272 >50  2.35 33

0.0245 >50  3.88 34 not defined not defined not defined not defined 35

0.0345 >50 19.66 36

0.0172 35.22  2.39 37 not defined not defined not defined not defined 38

0.0609 47.10 11.35 39 not defined not defined not defined not defined 40

0.0343 31.43  8.95 41

0.1638 >50 42.82 42

0.0167 >50  0.55 43

0.0649 >50 15.05 44 not defined not defined not defined not defined 45

0.0147 45.21  2.04 46 not defined not defined not defined not defined 47

0.0067 25.97  4.77 48

0.0556 >50 16.86 49

0.0148 >50  2.78 50

0.0554 47.95  9.52 51

0.3660 49.83 20.87 52

0.0413 >50 >50 53

0.0139 >50 34.12 54

0.0892 >50 16.00 55

0.0436 >50  3.07 56

0.0939 >50  8.94 57

0.0901 >50 31.97 58

0.0366 >50 17.10 59

0.1437 >50 46.20 60

0.1448 34.70  9.75 61

0.4749 >50 48.10 62

0.0193 >50  4.78 63

0.0473 >50 13.24 64

0.0258 >50 21.62 65

0.0211 >50 14.85 66

0.0385 >50  4.44 67

0.0152 >50  1.68 68

0.0652 >50 22.43 69

0.1973 >50 45.15 70

0.0345 >50 16.99 71

0.0150 >50  7.65 72

0.0526 >50 19.59 73

0.0224 49.10  4.17 74

0.0322 >50 11.15 75

0.0998  8.54  1.59 76

0.0583 46.20 14.80 77

0.0498 43.38  3.75 78

0.0359 >50 22.04 79

0.0364 >50 26.74 80

0.0224 39.74  1.11 81

0.0240 48.40  5.24 82

0.0483 >50  7.78 83

0.7324 >50 25.60 84 not defined not defined not defined not defined

6. COMPARISON OF SYK-INHIBITORY CAPACITY AND OF SYK-SELECTIVITY OF THECOMPOUNDS OF THE INVENTION COMPARED TO SELECTED COMPOUNDS OF WO2013/014060 AND OF WO 2011/092128

To have an efficient SYK-inhibitory capacity is not the only importantaspect which a SYK-inhibitor to be used as a medicament to treatSYK-related diseases must show. Similarly important like the lowIC₅₀-value with regard to SYK-inhibition (IC₅₀ (SYK)≦1 μM) is that thecandidate compound does not show undesired inhibitory effects on otherkinases which could lead to unwanted or even dangerous side effects.Examples of such other kinases that should not be inhibited by thecandidate SYK-inhibitor are AURB, FLT3 and GSKbeta.

Consequently the IC₅₀-values with regard to SYK, AURB, FLT3 and GSKbetafor structurally close compounds disclosed in WO 2013/014060 and of WO2011/092128 have been experimentally determined according to the sameassays as described in chapter 5. The measured IC₅₀-values with regardto SYK, AURB, FLT3 and GSKbeta of these structurally closest prior artcompounds are in the following tables 2a to 6c compared to therespective previously determined IC₅₀-values of a representativeselection of compounds of the invention (same assay conditions).

Further it is desirable for an SYK-inhibitor that is sufficientlySYK-specific as described above to have certain human liver microsomalstability (corresponding to CI<60% Q_(h);Q_(h)=liver blood flow).Otherwise it will be difficult to reach an adequate plasma level of theSYK-inhibitor in the patient to be treated. Consequently also theCI-values for structurally close compounds disclosed in WO 2013/014060and in WO 2011/092128 have been experimentally determined according tothe same human liver microsomal-test as described in chapter 5. Anexperimentally determined CI-value of more than 60% Q_(h) is regarded tobe inacceptable in order to reach an adequate plasma level of therespective SYK-inhibitor in the patient to be treated.

6.1 Comparisons for Compounds with Alkyl-Substituted Pyrazole Structures

Whereas all compounds of the invention (see Table 2a) and of WO2013/014060 (see Table 2b) with alkyl-substituted pyrazole structureshave suitable IC₅₀ (SYK)-values of smaller than 1 μM, only the compoundsof the invention (see Table 2a) have IC₅₀-values with regard to AURB ofmore than 50 μM (compared to IC₅₀-values (AURB) of significantly below 5μM for the compounds of WO 2013/014060 in Table 2b). Also theIC₅₀-values with respect to FLT3 are larger for the compounds of theinvention (Table 2a) compared to the compounds of WO 2013/014060 (seeTable 2b). Consequently the compounds of the invention withalkyl-substituted pyrazole structures are not only efficientSYK-inhibitors (like the compounds of WO 2013/014060 (see Table 2b)),but also do not have unwanted inhibitory effects on other kinases suchas AURB, FLT3 and GSK3beta (unlike the compounds of WO 2013/014060 (seeTable 2b)). The compounds of the invention with alkyl-substitutedpyrazole structures therefore show a significantly improvedSYK-selectivity compared to the structurally closest compounds disclosedin WO2013/014060.

TABLE 2a compounds of the invention with alkyl-substituted pyrazolestructures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM somal Ex.(SYK- (AURB- (FLT3- (GSK3beta- stability No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]  2

0.0144 >50 14.8 >10 <23 18

0.0046 >50 13.4 >10 <23 n.d. = not detected

TABELLE 2b Compounds of WO 2013/014060 with alkyl-substituted pyrazolestructures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM somal Ex.(SYK- (AURB- (FLT3- (GSK3beta- stability No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 112

0.006 2.96 1.25 >10 <23 114

0.0002 2.54 0.049 >10 26 115

0.0002 0.021 0.041 >10 <236.2 Comparisons for Compounds with Optionally Substituted BicyclicHeteroaryl Structures

Whereas all compounds of the invention (see Table 3a) and of WO2013/014060 (see Table 3b) with optionally substituted bicyclicheteroaryl structures have suitable IC₅₀ (SYK)-values of smaller than 1μM, only the compounds of the invention (see Table 3a) have IC₅₀-valueswith regard to AURB of more than 30 μM, most of them even of more than50 μM (compared to IC₅₀-values (AURB) of mostly below 1 μM for thecompounds of WO 2013/014060 in Table 3b). Consequently the compounds ofthe invention with optionally substituted bicyclic heteroaryl structuresare not only efficient SYK-inhibitors (like the compounds of WO2013/014060 (see Table 3b)), but also do not have unwanted inhibitoryeffects on other kinases such as AURB (unlike the compounds of WO2013/014060 (see Table 3b)).

The compounds of the invention with optionally substituted bicyclicheteroaryl structures therefore show a significantly improvedSYK-selectivity compared to the structurally closest compounds disclosedin WO2013/014060.

TABELLE 3a Compounds of the invention with optionally substitutedbicyclic heteroaryl structures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μMIC₅₀ in μM somal Ex. (SYK- (AURB- (FLT3- (GSK3beta- stability No.Structure Inhibition) Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]62

0.0193 >50 4.78 >10 <23 72

0.0526 >50 19.6 1.45 <23 36

0.0172 35.22 2.39 >10 <23 28

0.0335 >50 3.69 >10 <23 n.d. = not detected

TABELLE 3b Compounds of WO 2013/014060 with optionally substitutedbicyclic heteroaryl structures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μMIC₅₀ in μM somal Ex. (SYK- (AURB- (FLT3- (GSK3beta- stability No.Structure Inhibition) Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]29

0.002 0.293 0.315 >10 44 41

0.001 0.308 0.505 >10 37 42

0.002 0.630 0.618 >10 <23 61

0.002 0.250 0.411 >10 <23 81

0.003 0.949 0.514 >10 <23 85

0.002 0.460 0.321 6.82 49 94

0.001 0.298 0.267 n.d. n.d. 105

0.001 0.479 0.309 >10 64 107

0.009 1.82  1.76  >10 38 109

0.001 0.260 0.330 >10 416.3 Comparisons for Compounds with Alkoxy-Substituted Phenyl Structures

All compounds of the invention (see Table 4a), of WO 2011/092128 (seeTable 4b) and of WO 2013/014060 (see Table 4c) with alkoxy-substitutedphenyl structures have suitable IC₅₀ (SYK)-values of smaller than 1 μM.However, whereas the compounds of the invention (see Table 4a) haveIC₅₀-values with regard to AURB of more than 45 μM, often even of morethan 50 μM, the IC₅₀-values (AURB) of WO 2011/092128 (see Table 4b) andof WO 2013/014060 (see Table 4c) are mostly ≦5 μM, often even below 1 μMand consequently the compounds of the invention with alkoxy-substitutedphenyl structures have less unwanted inhibitory effects on other kinasessuch as AURB compared to most of the compounds of WO 2011/092128 (Table4b) and of WO 2013/014060 (see Table 4c).

Only example 8 of WO 2011/092128 (see Table 4b) also shows an IC₅₀-value(with regard to AURB) of more than 50 μM which seems comparable to thecompounds of the instant invention, however example 8 of WO 2011/092128(see Table 4b) shows with CI=77% Q_(h) a human liver microsomalstability of significantly lower than 60% Q_(h) that would lead to aninadequately low plasma level of the SYK-inhibitor in a patient to betreated. Also example 2 of WO2013/014060 (see Table 4c) shows with IC₅₀(AURB)=16.9 μM a slightly larger IC₅₀-value with respect to AURB thanthe other prior art compounds, however also here the human livermicrosomal stability is with CI=81% Q_(h) inadequate. In contrast tothat the compounds of the invention with alkoxy-substituted phenylstructures (see Table 4a) show acceptable CI-values of lower than 60%Q_(h) (all CI=<23)% Q_(h)).

The compounds of the invention with alkoxy-substituted phenyl structurestherefore show a significantly improved SYK-selectivity and additionallyan acceptable human liver microsomal stability compared to all of thestructurally closest compounds disclosed in WO2013/014060 and inWO2011/092128.

TABELLE 4a Compounds of the invention with alkoxy-substituted phenylstructures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM somal Ex.(SYK- (AURB- (FLT3- (GSK3beta- stability No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 1

0.0160 >50 3.99 >10 <23 8

0.0274 >50 13.50 >10 <23 52

0.0413 >50 >50 >10 <23 81

0.0240 48.40 5.24 >10 <23 n.d. = not determined

TABELLE 4b Compounds of WO 2011/092128 with alkoxy-substituted phenylstructures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM somal Ex.(SYK- (AURB- (FLT3- (GSK3beta- stability No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 35

0.001 5.21 1.18 >10 62 7

0.002 2.33 0.452 >10 79 8

0.012 >50 >50 >10 77 4

0.003 1.85 0.633 >10 33 1

0.009 5.09 1.53 >10 n.d. n.d. = not determined

TABELLE 4c Compounds of 2013/014060 with alkoxy-substituted phenylstructures micro- IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM somal Ex.(SYK- (AURB- (FLT3- (GSK3beta- stability No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 2

0.007 16.9 7.39 >10 81 8

0.001 0.643 0.369 >10 58 10

0.001 0.271 0.312 >10 57 11

0.002 0.752 0.738 >10 24 102

0.013 2.63 2.27 >10 546.4 Comparisons for Compounds with Heterocycle-Substituted orHeterocycle-Annulated Phenyl Structures

Whereas all compounds of the invention (see Table 5a), of WO 2013/014060(see Table 5b) with heterocycle-substituted or heterocycle-annulatedphenyl structures have suitable IC₅₀ (SYK)-values of smaller than 1 μM,only the compounds of the invention (see Table 5a) have IC₅₀-values withregard to AURB of mostly more than 45 μM, mostly of more than 50 μM(compared to IC₅₀-values (AURB) of below 1 μM for the compounds of WO2013/014060 in Table 5b). Consequently the compounds of the inventionwith heterocycle-substituted or heterocycle-annulated phenyl structuresare not only efficient SYK-inhibitors (like the compounds of WO2013/014060 (see Table 5b)), but also do not have unwanted inhibitoryeffects on other kinases such as AURB (unlike the compounds of WO2013/014060 (see Table 5b)).

The compounds of the invention with heterocycle-substituted orheterocycle-annulated phenyl structures therefore show a significantlyimproved SYK-selectivity compared to the structurally closest compoundsdisclosed in WO2013/014060.

Tabelle 5a: Compounds of the invention with heterocycle-substituted orheterocycle-annulated phenyl structures IC₅₀ in μM IC₅₀ in μM IC₅₀ in μMIC₅₀ in μM microsomal (SYK- (AURB- (FLT3- (GSK3beta- stability Ex. No.Structure Inhibition) Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]22

0.0128 46.90 1.17 >10 25 26

0.0258 >50 0.95 >10 <23 42

0.0167 >50 0.55 >10 <23 67

0.0152 >50 1.68 >10 34

Tabelle 5b: Compounds of WO 2013/014060 with heterocycle-substituted orheterocycle-annulated phenyl structures IC₅₀ in μM IC₅₀ in μM IC₅₀ in μMIC₅₀ in μM microsomal (SYK- (AURB- (FLT3- (GSK3beta- stability Ex. No.Structure Inhibition) Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]43

0.001 0.144 0.157 n.d. <23 76

0.002 0.075 0.169 >10 <23 101

0.002 1.05 0.140 >10 <236.5 Comparisons for Compounds with Optionally Substituted PyridineStructures

Whereas all compounds of the invention (see Table 6a), of WO 2011/092128(see Table 6b) and of WO 2013/014060 (see Table 6c) with optionallysubstituted pyridine structures have suitable IC₅₀ (SYK)-values ofsmaller than 1 μM, only the compounds of the invention (see Table 6a)have IC₅₀-values with regard to AURB of more than 49 μM, mostly even ofmore than 50 μM (compared to IC₅₀-values (AURB) of around 1 μM for thecompounds of WO 2011/092128 in Table 6b and of WO 2013/014060 in Table6c). Consequently the compounds of the invention with optionallysubstituted pyridine structures are not only efficient SYK-inhibitors(like the compounds of WO 2011/092128 (Table 6b) and of WO 2013/014060(see Table 6c)), but also do not have unwanted inhibitory effects onother kinases such as AURB (unlike the compounds of WO 2011/092128(Table 6b) and of WO 2013/014060 (see Table 6c)).

The compounds of the invention with optionally substituted pyridinestructures therefore show a significantly improved SYK-selectivitycompared to the structurally closest compounds disclosed in WO2011/092128 or in WO2013/014060.

TABLE 6a Compounds of the invention with optionally substituted pyridinestructures IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM microsomal (SYK-(AURB- (FLT3- (GSK3beta- stability Ex. No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 59

0.1437 >50 46.20 >10 <23 61

0.4749 >50 48.10 >10 <23 51

0.3660 49.83 20.87 >10 <23 41

0.1638 >50 42.82 >10 <23 27

0.1382 >50 26.64 >10 <23 n.d. = not determined

TABLE 6b Compound of WO 2011/092128 with optionally substituted pyridinestructure IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM microsomal (SYK-(AURB- (FLT3- (GSK3beta- stability Ex. No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)]  3

0.0122 1.04 1.82 >10 24 45

0.0002 0.086 0.100 >10 53

TABLE 6c Compound of WO 2013/014060 with optionally substituted pyridinestructure IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM microsomal (SYK-(AURB- (FLT3- (GSK3beta- stability Ex. No. Structure Inhibition)Inhibition) Inhibition) Inhibition) Cl [% Q_(h)] 6

0.004 1.03 0.640 >1 24

6. INDICATIONS

As has been found, the compounds of formula 1 are characterised by theirrange of applications in the therapeutic field. Particular mentionshould be made of those applications for which the compounds of formula1 according to the invention are preferably used on the basis of theirpharmaceutical activity as Syk-inhibitors. Examples include respiratorycomplaints, allergic diseases, osteoporosis, gastrointestinal diseasesor complaints, immune or autoimmune diseases, allergic diseases,inflammatory diseases, e.g. inflammatory diseases of the joints, skinand eyes and diseases of the peripheral or central nervous system.

Particular mention should be made of the prevention and treatment ofrespiratory tract and pulmonary diseases which are accompanied byincreased mucus production, inflammation and/or obstructive diseases ofthe airways. Examples of these include asthma, paediatric asthma, ARDS(Adult Respiratory Distress Syndrome), acute, allergic or chronicbronchitis, autoimmune haemolytic anemia, chronic obstructive bronchitis(COPD) (including the treatment of Rhinovirus-induced exacerbations),coughs, allergic rhinitis or sinusitis, allergic rhinoconjunctivitis,chronic rhinitis or sinusitis, alveolitis, farmers lung, hyperreactiveairways, infectious bronchitis or pneumonitis, bronchiectasis, pulmonaryarterial hypertension, pulmonary fibrosis, bronchial oedema, pulmonaryoedema, pneumonia or interstitial pneumonia triggered by various causessuch as aspiration, inhalation of toxic gases or bronchitis, pneumoniaor interstitial pneumonia triggered by cardiac insufficiency, radiation,chemotherapy, cystic fibrosis or mucoviscidosis, alpha 1-antitrypsindeficiency.

The compounds according to the invention are preferably also suitablefor the treatment of allergic diseases such as for example allergicrhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, andcontact dermatitis, urticaria/angiooedema and allergic dermatitis.

Mention should also preferably be made of the treatment of inflammatorydiseases of the gastrointestinal tract. Examples of these are Crohn'sdisease and ulcerative colitis.

The compounds according to the invention are preferably also suitablefor the treatment of inflammatory diseases of the joints, of the bloodvessels and of the kidney or inflammatory diseases of the skin and eyes.Examples of these are rheumatoid arthritis, antibody-basedglomerulonephritis, psoriasis, Kawasaki syndrome, coeliac disease(sprue), arteriosclerosis and Wegener's granulomatosis, osteoarthritis,systemic scleroderma, ankylosing spondylitis.

The compounds according to the invention are preferably also suitablefor the treatment of autoimmune diseases. Examples of these arehepatitis (autoimmune-based), lupus erythematodes, lupus nephritis,systemic lupus, Systemic lupus erythematosus, discoid lupus, cutaneouslupus erythematosus (acute, subacute, chronic), anti-phospholipidsyndrome, Berger's disease, Evans's syndrome, immunohaemolytic anaemia,ITP (idiopathic thrombocytopenic purpura; adult, neonatal andpaediatric), myasthenia gravis, Sjögren's syndrome, sclerodermy, Bullouspemphigoid and Pemphigus vulgaris.

The compounds according to the invention are preferably also suitablefor the treatment of B-cell lymphomas, like chronic lymphocyticleukaemia and non-Hodgkin's lymphomas or T cell lymphomas.

The compounds according to the invention are preferably also suitablefor the treatment of Graft-versus-host disease.

Mention may preferably also be made of the prevention and treatment ofdiseases of the peripheral or central nervous system. Examples of theseare acute and chronic multiple sclerosis or non-familial lateralsclerosis.

Mention may preferably also be made of the prevention and treatment ofosteoporotic diseases such as for example disease-associated osteopenia,osteoporosis and osteolytic diseases.

The present invention relates particularly preferably to the use ofcompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of diseases selected from among asthma, COPD, allergicrhinitis, Adult Respiratory Distress Syndrome, bronchitis, allergicdermatitis, contact dermatitis, ITP, rheumatoid arthritis, systemiclupus erythematosus, lupus nephritis, and allergic rhinoconjunctivitis.

Most preferably, the compounds of formula 1 may be used for thetreatment of a disease selected from among asthma, allergic rhinitis,rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis,allergic dermatitis and COPD.

7. COMBINATIONS

The compounds of formula 1 may be used on their own or in conjunctionwith other active substances of formula 1 according to the invention.The compounds of formula 1 may optionally also be used in conjunctionwith other pharmacologically active substances. Preferably the activesubstances used here may be selected for example from among thebetamimetics, anticholinergics, corticosteroids, PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists, iNos-inhibitos, HMG-CoA reductaseinhibitors (statins), PI3-kinase-inhibitors, CCR3-antagonists,CCR2-antagonists, CCR1-antagonists, IKK2-inhibitors, A2a agonists,alpha-4-integrin-inhibitors, CRTH2-antagonists, histamine 1, combinedH1/H3-antagonists, p38 kinase inhibitors, methylxanthines,ENaC-inhibitors, CXCR1-antagonists, CXCR2-antagonists, ICE-inhibitors,LTB4-antagonists, 5-LO antagonists, FLAP-antagonists. LTB4-antagonists;cromoglycine, dissociated glucocorticoid mimetics, immunesuppressiveagents, cytostatica, non-steroidal anti-inflammatory drugs (NSAIDs),chloroquine, hydroxychloroquine, anti-TNF-antibodies, anti-GM-CSFantibodies, anti-CD46-antibodies, anti-IL-1-antibodies,anti-IL-2-antibodies, anti-IL-4-antibodies, anti-IL-5-antibodies,anti-1L6 antibodies, anti-IL6 receptor antibodies,anti-IL-13-antibodies, anti-IL_18 antibodies, anti-CD30 L antibodies,anti-Ox40L-antibodies, anti-IL-4/IL-13-antibodies, anti-IL-23 (p19)antibodies, anti-IL-12/IL-23 (p40) antibodies, anti-CD3 antibodies,anti-CD4 antibodies, anti-CD154 antibodies, CD89 antibodies, anti-IL-2receptor/CD25 antibodies, anti-CD22 antibodies, anti-interferonantibodies, anti-ICOS antibodies, anti-ICOS antibodies, anti-CD20antibodies, anti-CD40 antibodies, anti-BAFF/BLyS antibodies, anti-CD18antibodies, anti-CD62L antibodies, anti-CD147 antibodies, anti-integrinantibodies, agents interfering with LFA-1, IL-36 pathway modulators,M-CSF/c-fms antagonists, CTLA-4 fusions, mTor modulators, Toll likereceptors 7 inhibitors (TLR7 inhibitor), Toll like receptor 9 inhibitors(TLR9 inhibitors), T cell-costimulatory modulators such as CTLA-4fusions, JAK inhibitors, IRF modulators, CX3 chemokine receptorantagonists (CX3CR1 antagonists), IRAK inhibitors (in particular IRAK1-and IRAK4-inhibitors), Sphingosine-1-phosphate modulators (S1P pathwaymodulators),

or double or triple combinations thereof, such as for examplecombinations of one, two or three compounds selected from among the

-   -   Syk-inhibitors of formula 1, betamimetics, corticosteroids,        EGFR-inhibitors and PDE4-antagonists,    -   Syk-inhibitors of formula 1, anticholinergics, betamimetics,        corticosteroids, EGFR-inhibitors and PDE4-antagonists,    -   Syk-inhibitors of formula 1, PDE4-inhibitors, corticosteroids        and EGFR-inhibitors,    -   Syk-inhibitors of formula 1, EGFR-inhibitors and        PDE4-inhibitors,    -   Syk-inhibitors of formula 1 and EGFR-inhibitors,    -   Syk-inhibitors of formula 1, betamimetics and anticholinergics    -   Syk-inhibitors of formula 1, anticholinergics, betamimetics,        corticosteroids and PDE4-inhibitors,    -   Syk-inhibitors of formula 1, anticholinergics, betamimetics,        corticosteroids, iNOS inhibitors, HMG-CoA reductase inhibitors.

Combinations of three active substances each taken from one of theabove-mentioned categories of compounds are also an object of theinvention.

Suitable betamimetics used are preferably compounds selected from amongarformoterol, carmoterol, formoterol, indacaterol, salmeterol,albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin,levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol,orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin,salmefamol, soterenol, sulphonterol, terbutalin, tiaramide, tolubuterol,zinterol,6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(2,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(3,5-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(4-Fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;N-(5-{2-[3-(4,4-Diethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[3-(4,4-Diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[3-(4,4-Diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[1,1-Dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazine-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;8-{2-[1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(2-oxo-5-trifluormethyl-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide;8-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinoline-2-one;8-Hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinoline-2-one;5-[(1R)-2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one;[3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea;4-((1R)-2-{6-[2-(2,6-Dichlor-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol;3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide;3-(3-{7-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulfonamide;4-((1R)-2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol;Vilanterol;N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;2-(3-{2-[2-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-propyl}-phenyl)-N-[4-(4-hydroxy-phenyl)-2-vinyl-penta-2,4-dienyl]-acetamide;(1R)-5-{2-[6-(2,2-Difluor-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinoline-2-one;(R,S)-4-(2-{[6-(2,2-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl) phenol;(R,S)-4-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(4,4-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinoline-2(1H)-one;(R,S)-[2-({6-[2,2-Difluor-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;4-(1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5I5-tetrafluor-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol;(R,S)-[5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide;(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(R,S)—N-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea;3-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione;(R,S)-4-[2-({6-[2,2-Difluor-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;5-((1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinoline-2(1H)-one;4-((1R)-2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(3,3-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-(2-{[6-(2,2-Difluor-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(2,2-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;3-[2-(3-Chlor-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;7-[2-(2-{3-[2-(2-Chlor-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from among

tiotropium salts, particularly the bromide salt, oxitropium salts,particularly the bromide salt, flutropium salts, particularly thebromide salt, ipratropium salts, particularly the bromide salt,Aclidinium salts, particularly the bromide salt, glycopyrronium salts,particularly the bromide salt, trospium salts, particularly the chloridesalt, tolterodin,(3R)-1-Phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octan-salts;2,2-Diphenyl propionic acid tropenole ester-methobromide; 2,2-Diphenylpropionic acid scopine ester-methobromide; 2-Fluor-2,2-Diphenyl aceticacid scopine ester-methobromide; 2-Fluor-2,2-Diphenyl acetic acidtropenole ester-methobromide; 3,3′,4,4′-Tetrafluor benzilic acidtropenole ester-methobromide; 3,3′,4,4′-Tetrafluor benzilic acid scopineester-methobromide; 4,4′-Difluor benzilic acid tropenoleester-methobromide; 4,4′-Difluor benzilic acid scopineester-methobromide; 3,3′-Difluor benzilic acid tropenoleester-methobromide; 3,3′-Difluor benzilic acid scopineester-methobromide; 9-Hydroxy-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Fluor-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Hydroxy-fluorene-9-carboxylic acid scopineester-methobromide; 9-Fluor-fluorene-9-carboxylic acid scopineester-methobromide; 9-Methyl-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Methyl-fluorene-9-carboxylic acid scopineester-methobromide; Benzilic acid cyclopropyltropine ester-methobromide;2,2-Diphenyl propionic acid cyclopropyltropine ester-methobromide;9-Hydroxy-xanthene-9-carboxylic acid cyclopropyltropineester-methobromide; 9-Methyl-fluorene-9-carboxylic acidcyclopropyltropine ester-methobromide; 9-Methyl-xanthene-9-carboxylicacid cyclopropyltropine ester-methobromide;9-Hydroxy-fluorene-9-carboxilic acid cyclopropyltropineester-methobromide; 4,4′-Difluor benzilic acid methyl estercyclopropyltropine ester-methobromide; 9-Hydroxy-xanthene-9-carboxylicacid tropenole ester-methobromide; 9-Hydroxy-xanthene-9-carboxylic acidscopine ester-methobromide; 9-Methyl-xanthene-9-carboxylic acidtropenole ester-methobromide; 9-Methyl-xanthene-9-carboxylic acidscopine ester-methobromide; 9-Ethyl-xanthene-9-carboxylic acid tropenoleester-methobromide; 9-Difluormethyl-xanthene-9-carboxylic acid tropenoleester-methobromide; 9-Hydroxymethyl-xanthene-9-carboxylic acid scopineester-methobromide;

-   3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;-   N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;-   7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one    and Darotropium;    optionally in the form of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium, aclidinium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from among

beclomethasone, betamethasone, budesonide, butixocort, ciclesonide,deflazacort, dexamethasone, etiprednole, flunisolide, fluticasone,loteprednole, mometasone, prednisolone, prednisone, rofleponide,triamcinolone, tipredane; Pregna-1,4-diene-3,20-dione,6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-, (6-alpha, 11-beta,16-alpha)-(9CI);16,17-butylidenedioxy-6,9-difluoro-1-hydroxy-17-(methylthio)androst-4-en-3-one;6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-1-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothioneacid (S)-fluoromethylester; (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate;6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylicacid cyanomethyl ester, each optionally in the form of the racemates,enantiomers or diastereomers thereof and optionally in the form of thesalts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the steroid is selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulfobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

PDE4 inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram,oglemilast, tetomilast;5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-Quinoline(D-4418);5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-Quinoline(D-4396 (Sch-351591));N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylicacid amide (AWD-12-281 (GW-842470));9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-Purin-6-amine(NCS-613);4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-Pyridine(CDP-840);N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-Pyridinecarboxamide(PD-168787);4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-Pyridinone(T-440);2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-(2H)-Phthalazinone(T-2585);(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine(V-11294A);beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-Isoindole-2-propanamide(CDC-801); Imidazo[1,5-a]pyrido[3,2-e]pyrazine-6(5H)-one,9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888);5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-,(3S,5S)-2-Piperidinon (HT-0712);4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol (L-826141);N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluormethoxy-3-cyclopropylmethoxybenzamide;(−)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide;(R)-(+)-1-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon;3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N′—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidon;cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid];2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-1-ol];(R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat;(S)-(−)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat;9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin;9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin,

optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast;(E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one(MEN-91507);4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyricacid (MN-001);1-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid;1-(((1(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid;[2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid,

optionally in the form of the racemates, enantiomers or diastereomers,optionally in the form of the pharmacologically acceptable acid additionsalts and optionally in the form of the salts and derivatives, solvatesand/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-butene-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidine-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesuiphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoine,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidine-1-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazolin;4-{2-[4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-ethyl}-6-methyl-morpholine-2-one,4-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cylohexyl}-1-methyl-piperazine-2-one,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesuphonyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidine-4-yloxy-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidine-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline,3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline,[4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,cetuximab, trastuzumab, panitumumab (=ABX-EGF), Mab ICR-62, gefitinib,pelitinib, canertinib and erlotinib, optionally in the form of theracemates, enantiomers or diastereomers thereof, optionally in the formof the pharmacologically acceptable acid addition salts thereof, thesolvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, olopatadine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong lexipafant,4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.Any reference to the above-mentioned above-mentioned PAF-antagonistsincludes within the scope of the present invention a reference to anypharmacologically acceptable acid addition salts thereof which mayexist.

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) preferablyinclude compounds selected from among Aceclofenac, Acemetacin,Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam,Antolmetinguacil, Anirolac, Antrafenin, Azapropazon, Benorilat,Bermoprofen, Bindarit, Bromfenac, Bucloxinsäure, Bucolom, Bufexamac,Bumadizon, Butibufen, Butixirat, Carbasalatcalcium, Carprofen, CholinMagnesium Trisalicylat, Celecoxib, Cinmetacin, Cinnoxicam, Clidanac,Clobuzarit, Deboxamet, Dexibuprofen, Dexketoprofen, Diclofenac,Diflunisal, Droxicam, Eltenac, Enfenaminsäure, Etersalat, Etodolac,Etofenamat, Etoricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac,Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin,Flufenaminsaure, Flufenisal, Flunoxaprofen, Flurbiprofen,Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac,Ibuprofen, Indobufen, Indometacin, Indometacinfarnesil, Indoprofen,Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac,Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsaure, Meclofen,Mefenaminsaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton,Naproxen, Nifluminsaure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon,Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac,Priroxicam, Pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin,Proquazon, Protizininsaure, Rofecoxib, Romazarit, Salicylamid,Salicylsaure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam,Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin,Tiaprofensaure, Taramid, Tilnoprofenarbamel, Timegadin, Tinoridin,Tiopinac, Tolfenaminsaure, Tolmetin, Ufenamat, Valdecoxib, Ximoprofen,Zaltoprofen und Zoliprofen.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, glycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate,methotrexate,((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurineriboside, probenecid, sildenafil, sulfinpyrazone,taurochenodeoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsinand zaprinast, dipyridamole, optionally in the form of the racemates,enantiomers, diastereomers and the pharmacologically acceptable acidaddition salts and hydrates thereof.

Examples of JAK inhibitors preferably include compounds selected fromamong Tofacitinib and Ruxolitinib.

Examples of immunesuppressive agents preferably include compoundsselected from among mycophenolate mofetil, mycophenolic acid,azathioprine, cyclosporine, tacrolimus, pimecrolimus, abetimus,gusperimus and leflunomide.

An example of a cytostaticum is cyclophosphamide.

The invention relates more preferably to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for treating respiratorycomplaints, containing the Syk-inhibitors of formula 1 andMRP4-inhibitors according to the invention, the MRP4-inhibitorspreferably being selected from among dehydroepiandrosterone 3-sulphate,estradiol 3,17-disulphate, flurbiprofen, indomethacin, indoprofen,taurocholate, optionally in the form of the racemates, enantiomers,diastereomers and the pharmacologically acceptable acid addition saltsand hydrates thereof. The separation of enantiomers from the racematescan be carried out using methods known from the art (e.g. chromatographyon chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the Syk-inhibitors of formula 1,MRP4-inhibitors and another active substance according to the invention,such as, for example, an anticholinergic, a PDE4 inhibitor, a steroid,an LTD4-antagonist or a betamimetic, and the preparation thereof and theuse thereof for treating respiratory complaints.

Compounds which may be used as iNOS inhibitors are compounds selectedfrom among: S-(2-aminoethyl)isothiourea, aminoguanidine,2-aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1,3-Thiazine-2-amine(=AMT), L-canavanine, 2-iminopiperidine, S-isopropylisothiourea,S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrullin,S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME(N^(ω)-nitro-L-argininemethylester), L-NMMA(N^(G)-monomethyl-L-arginine), L-NIO (N^(ω)-iminoethyl-L-ornithine),L-NIL (N^(ω)-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoicacid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,1686-1689), N-[[3-(aminomethyl)phenyl]methyl]-Ethanimidamide (=1400W),(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S.4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine suchas e.g. (1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidine-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmaco Exp. Ther. 2002, 303, 52-57),3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Examples of iNOS-inhibitors within the scope of the present inventionmay also include antisense oligonucleotides, particularly thoseantisense oligonucleotides which bind iNOS-coding nucleic acids. Forexample, WO 01/52902 describes antisense oligonucleotides, particularlyantisense oligonucleotides, which bind iNOS coding nucleic acids, formodulating the expression of iNOS. iNOS-antisense oligonucleotides asdescribed particularly in WO 01/52902 may therefore also be combinedwith the PDE4-inhibitors of the present invention on account of theirsimilar effect to the iNOS-inhibitors.

Suitable HMG-CoA reductase inhibitors (also called statins) which may bepreferably used in double or triple combinations with the compounds offormula 1 are selected from among Atorvastatin, Cerivastatin,Flurvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin, optionally in form of their pharmaceutically available acidaddition salts, prodrugs, solvates or hydrates thereof.

8. FORMULATIONS

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula 1 according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula 1 areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula 1 are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula 1 have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula 1 are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the compounds of formula 1 dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols according to the invention areknown from the prior art. Suitable propellant gases are selected fromamong hydrocarbons such as n-propane, n-butane or isobutane andhalohydrocarbons such as preferably fluorinated derivatives of methane,ethane, propane, butane, cyclopropane or cyclobutane. The propellantgases mentioned above may be used on their own or in mixtures thereof.Particularly preferred propellant gases are fluorinated alkanederivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Thepropellant-driven inhalation aerosols used within the scope of the useaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

Propellant-Free Inhalable Solutions

The compounds of formula 1 according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including for example the wordsrespiratory disease, COPD or asthma, together with aimidazolyl-pyrimidine according to formula 1 and one or more combinationpartners selected from those described above.

The invention claimed is:
 1. A compound, which is

or a pharmaceutically acceptable salt thereof.
 2. A compound, which is

or a pharmaceutically acceptable salt thereof.
 3. A method of treatingasthma comprising the step of administering to a person in need thereofthe compound according to claim 1 or a pharmaceutically acceptable saltthereof.
 4. A method of treating COPD comprising the step ofadministering to a person in need thereof the compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 5. Apharmaceutical formulation comprising the compound according to claim 1or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 6. A pharmaceutical formulation comprising thecompound according to claim 2 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 7. A method oftreating asthma comprising the step of administering to a person in needthereof the compound according to claim 2 or a pharmaceuticallyacceptable salt thereof.
 8. A method of treating COPD comprising thestep of administering to a person in need thereof the compound accordingto claim 2 or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical formulation comprising the compound according to claim 1,or a pharmaceutically acceptable salt thereof, in combination with anactive substance selected from the group consisting of anticholinergics,betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors,LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, CRTH2-antagonists,HMG-CoA reductase inhibitors and NSAIDs.
 10. A pharmaceuticalformulation comprising the compound according to claim 2, or apharmaceutically acceptable salt thereof, in combination with an activesubstance selected from the group consisting of anticholinergics,betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors,LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, CRTH2-antagonists,HMG-CoA reductase inhibitors and NSAIDs.